FUSED BICYCLIC mTOR INHIBITORS

ABSTRACT

Compounds represented by Formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, are inhibitors of mTOR and useful in the treatment of cancer.

This application claims the benefit of U.S. Patent Application Nos.60/737,581 filed Nov. 17, 2005, and 60/854,247 filed Oct. 25, 2006.

BACKGROUND OF THE INVENTION

The present invention is directed to bicyclic compounds that areinhibitors of mammalian Target Of Rapamycin (mTOR) kinase (also known asFRAP, RAFT, RAPT, SEP). In particular, the present invention is directedto fused bicyclic compounds that are mTOR inhibitors useful in thetreatment of cancer.

International Patent Publication WO 2001 019828 describes thepreparation of heteroaromatic amines as protein kinase inhibitors.International Patent Publication WO 2005/047289 describespyrrolopyrimidine compounds useful in treatment of cancer. Bergstrom etal., J. Org. Chem., 56:5598-5602 (1991) describes Palladium-MediatedSynthesis of C-5 Pyrimidine Nucleoside Thioethers from Disulfides andMercurinucleosides.

It has been shown that high levels of dysregulated mTOR activity areassociated with variety of human cancers and several hamartomasyndromes, including tuberous sclerosis complex, the PTEN-relatedhamartoma syndromes and Peutz-Jeghers syndrome. Although rapamycinanalogues are in clinical development for cancer as mTOR kinaseinhibitor, the clinical out come with CCI-779 is just modest in breastand renal cancer patients. This is probably because rapamycin partiallyinhibits mTOR function through raptor-mTOR complex (mTORC1). It has beenalso found that 213 of the breast cancer and ½ of renal cancer patientsare resistant to rapamycin therapy. With a recent discovery ofrictor-mTOR complex (mTORC2) which is involved in phosphorylation of AKT(S473) that is important in regulation of cell survival and modulationof PKCα that plays a major role in regulation of actin cytoskeletalorganization in a rapamycin-independent manner, and inhibition of theseactivities of mTOR is probably important for broader antitumor activityand better efficacy. Therefore, it is desirable to develop novelcompounds that are direct inhibitors of mTOR kinase, which would inhibitmTORC1 and mTORC2.

Rapamycin, a macrolide antibiotic has been shown to specifically inhibitmTOR kinase activity in vitro and in vivo in several studies. Althoughprecise mechanism by which rapamycin inhibits mTOR function is not wellunderstood, it is known that rapamycin first binds to FKBP12 (FK506binding protein) and then binds to FRB domain of mTOR and thus inhibitmTOR activity by inducing conformational changes, which inhibitssubstrate binding. Rapamycin has been widely used as a specific mTORinhibitor in preclinical studies to demonstrate role of mTOR in signaltransduction and cancer. But rapamycin was not developed as a cancertherapy because of stability and solubility problems even thoughsignificant antitumor activity was observed in the NCI screeningprogramme. However, synthesis of rapamycin analogues with superiorsolubility and stability properties has led to run the clinical trailswith CCI-779, RAD001 and AP23573. The most advanced rapamycin analogue,CCI-779 has shown modest anti-tumor activity in Phase II breast renalcarcinoma and mantle cell lymphoma clinical trials.

The Tor genes were originally identified in yeast as the targets of thedrug rapamycin. The structurally and functionally conserved mammaliancounter part of yeast TOR, mTOR was later discovered. mTOR is a memberof the phosphoinositide kinase-related kinase (PIKK) family, but ratherthan phosphorylating phosphoinositides, phosphorylates proteins onserine or threonine residues. Genetic studies have shown that mTOR isessential for cell growth and development in fruit flies, nematodes andmammals, and the disruption of the genes encoding mTOR results inlethality in all species. Several studies have demonstrated that mTORhas a central role in controlling cell growth, proliferation andmetabolism. mTOR regulates a wide range of cellular functions, includingtranslation, transcription, mRNA turnover, protein stability, actincytoskeletal organization and autophagy. There are two mTOR complexes inmammalian cells. mTOR complex I (mTORC1) is a raptor-mTOR complex, whichmainly regulates cell growth in a rapamycin-sensitive manner whereasmTOR complex II (mTORC2) is a rictor-mTOR complex, which regulatescytoskeletal organization in a rapamycin-insensitive manner.

The best-characterized function of mTOR in mammalian cells is regulationof translation. Ribosomal S6 kinase (S6K) and eukaryotic initiationfactor 4E binding protein 1 (4E-BPI), the most extensively studiedsubstrates of mTOR, are key regulators of protein translation. S6K isthe major ribosomal protein kinase in mammalian cells. Phosphorylationof S6 protein by S6K selectively increases the translation of mRNAscontaining a tract of pyrimidines motif; these mRNAs often encoderibosomal proteins and other translational regulators. Thus, S6Kenhances overall translation capacity of cells. 4E-BP1, anotherwell-characterized mTOR target, acts as a translational repressor bybinding and inhibiting the eukaryotic translation initiation factor 4E(eIF4E), which recognizes the 5′ end cap of eukaryotic mRNAs.Phosphorylation of 4E-BP1 by mTOR results in a dissociation of 4E-BP1from eIF4E, thereby relieving the inhibition of 4E-BP1 oneIF4E-dependent translation initiation. eIF4E overexpression enhancescell growth and transforms cells by increasing the translation of asubset of key growth-promoting proteins, including cyclin D1, c-Myc andVEGF. Therefore, mTOR-dependent regulation of both 4E-BP1 and S6K mightbe one mechanism by which mTOR positively regulates cell growth. mTORintegrates two of the most important extracellular and intracellularsignals involved in the regulation of cell growth: growth factors andnutrients. Growth factor, such as insulin or IGF1 and nutrients, such asamino acids or glucose, enhance mTOR function, as evidenced by anincreased phosphorylation of S6K and 4E-BP1. Rapamycin or dominantnegative mTOR inhibits these effects, indicating that mTOR integratesthe regulation of signals from growth factors and nutrients.

Signalling pathways that are upstream and downstream of mTOR are oftenderegulated in variety of cancers, including breast, lung, kidney,prostate, blood, liver, ovarian, thyroid, GI tract and lymphoma.Oncogenes including overexpressed receptor tyrosine kinases andconstitutively activated mutant receptors activate PI3K-mediatedsignaling pathways. Additional alterations of the PI3K-mTOR pathway inhuman cancers include amplification of the p110 catalytic subunit ofPI3K, loss of PTEN phosphatase function, amplification of AKT2,mutations in TSC1 or TSC2, and overexpression or amplification of eIF4Eor S6K1. Mutation or loss of heterozygosity in TSC1 and TSC2 most oftengive rise to Tuberous Sclerosis (TSC) syndrome. TSC is rarely associatedwith malignant tumors, although patients with TSC are at risk formalignant renal cancer of clear-cell histology. Although inactivation ofTSC might not lead to malignancy per se, deregulation of this pathwayseems crucial for angiogenesis in developing malignancies. TSC2regulates VEGF production through mTOR-dependent and -independentmanner.

With the recent discovery of rapamycin independent function of mTOR (bymTOR2) in phosphorylation AKT (at S473) that is important in regulationof cell survival and modulation of PKCα, which plays a major role inregulation of actin cytoskeletal organization, it is believed thatinhibition of mTOR function by rapamycin is partial. Therefore,discovery of a direct mTOR kinase inhibitor, which would completelyinhibit the function of both mTORC1 and mTORC2, is required for broaderanti-tumor activity and better efficacy. Here we describe the discoveryof direct mTOR kinase inhibitors, which can be used in the treatment ofvariety of cancers—including breast lung, kidney, prostate, blood,liver, ovarian, thyroid, GI tract and lymphoma—and other indicationssuch as rheumatoid arthritis, hamartoma syndromes, transplant rejection,IBD, multiple sclerosis and immunosuppression.

Recent success of Tarceva™, an EGFR kinase inhibitor for the treatmentof NSCLC and prior success with Gleevec™ for the treatment of CMLindicate that it is possible to develop selective kinase inhibitors forthe effective treatment of cancers. Although there are severalanti-cancer agents including kinase inhibitors, there is stillcontinuing need for improved anti-cancer drugs, and it would bedesirable to develop new compounds with better selectivity, potency orwith reduced toxicity or side effects.

Thus, it is desirable to develop compounds that exhibit mTOR inhibitionin order to treat cancer patients. Further, such compounds may be activein other kinases such as, for example, PI3K, Src, KDR, to add efficacyin breast, non-small cell lung cancer (NSCLC), renal cell carcinoma,mantle cell lymphoma, endometrial cancers, or other hamartoma syndromes.

SUMMARY OF THE INVENTION

Compounds represented by Formula (I)

or a pharmaceutically acceptable salt thereof, are inhibitors of mTORand useful in the treatment of cancer.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are represented by Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

X₁, and X₂ are each independently N or C-(E¹)_(aa);

X₅ is N, C-E¹)_(aa), or N-(E¹)_(aa);

X₃, X₄, X₆, and X₇ are each independently N or C;

wherein at least one of X₃, X₄, X₅, X₆, and X₇ is independently N orN-(E¹)_(aa);

R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl, aminomethylcycloC₃₋₁₀alkyl,bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl or heterobicycloC₅₋₁₀alkyl any of which is optionallysubstituted by one or more independent G¹¹ substituents;

Q¹ is -A(R¹)_(m)B(W)_(n) or —B(G¹¹)_(n)A(Y)_(m);

A and B are respectively, 5 and 6 membered aromatic or heteroaromaticrings, fused together to form a 9-membered heteroaromatic systemexcluding 5-benzo[b]furyl and 3-indolyl; and excluding 2-indolyl,2-benzoxazole, 2-benzothiazole, 2-benzimidazolyl,4-aminopyrrolopyrimidin-5-yl, 4-aminopyrrolopyrimidin-6-yl, and7-deaza-7-adenosinyl derivatives when X₁ and X₅ are CH, X₃, X₆ and X₇are C, and X₂ and X₄ are N;

or Q¹ is -A(R¹)_(m)A(Y)_(m), wherein each A is the same or different5-membered aromatic or heteroaromatic ring, and the two are fusedtogether to form an 8-membered heteroaromatic system;

R¹ is independently, hydrogen, —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl,halogen, oxo, aryl(optionally substituted with 1 or more R³¹ groups),hetaryl(optionally substituted with 1 or more R³¹ groups), C₁₋₆alkyl,—C₀₋₈alkylC₃₋₈cycloalkyl, —C₀₋₈alkyl-NR³¹¹S(O)₀₋₂NR³²¹R³³¹,—C₀₋₈alkyl-S(O)₀₋₂NR³¹¹R³²¹, —C₀₋₈alkyl-NR³¹¹COR³²¹,—C₀₋₈alkyl-NR³¹¹CO₂R³²¹, —C₀₋₈alkyl-NR³¹¹CONR³²¹R³³¹,—C₀₋₈alkyl-CONR³¹¹R³²¹, —C₀₋₈alkyl-CON(R³¹¹)S(O)₀₋₂R³²¹,—C₀₋₈alkyl-CO₂R³¹¹, —C₀₋₈alkyl-S(O)₀₋₂R³¹¹, —C₀₋₈alkyl-O—C₁₋₈alkyl,—C₀₋₈alkyl-O—C₀₋₈alkylC₃₋₈cycloalkyl, C₀₋₈alkyl-O—C₀₋₈alkylheterocyclyl,—C₀₋₈alkyl-O—C₀₋₈alkylaryl, —C₀₋₈alkylaryl, —C₀₋₈alkylhetaryl,—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-S—C₀₋₈alkyl, —C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylheterocyclyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylaryl, —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylhetaryl,—CO₀₋₈alkyl-NR³¹¹R³²¹, —C₂₋₈alkenyl, —C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃,OCHF₂; provided that Q¹ is not N-methyl-2-indolyl,N-(phenylsulfonyl)-2-indolyl, or N-tert-butoxycarbonyl

W is independently, hydrogen, —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl,halogen, oxo, aryl (optionally substituted with 1 or more R³¹ groups),hetaryl (optionally substituted with 1 or more R³¹ groups), C₁₋₆alkyl,—C₀₋₈alkylC₃₋₈cycloalkyl, —C₀₋₈alkyl-NR³¹²S(O)₀₋₂R³²²,—C₀₋₈alkyl-NR³¹¹S(O)₀₋₂NR³²¹R³³¹, —C₀₋₈alkyl-NR³¹¹CO₂R³²¹,—C₀₋₈alkyl-CON(R³¹¹)S(O)₀₋₂R³²¹, —C₀₋₈alkyl-S(O)₀₋₂NR³¹²R³²²,C₀₋₈alkyl-NR³¹²COR³²², —C₀₋₈alkyl-NR³¹²CONR³²²R³³²,—C₀₋₈alkyl-CONR³¹²R³²², —C₀₋₈alkyl-CO₂R³¹², —C₀₋₈alkylS(O)₀₋₂R³¹²,—C₀₋₈alkyl-O—C₁₋₈alkyl, —C₀₋₈alkyl-O—C₀₋₈alkylcyclyl,—C₀₋₈alkyl-O—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-O—C₀₋₈alkylaryl,-Oaryl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl, —C₀₋₈alkylaryl,—C₀₋₈alkylhetaryl, —C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-S—C₀₋₈alkyl,—C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(R³¹²)—C₀₋₈alkyl,—C₀₋₈alkyl-N(R³¹²)—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(R³¹²)—C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-N(R³¹²)—C₀₋₈alkylaryl, —C₀₋₈alkyl-N(R³¹²)—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-NR³¹²R³²², —C₂₋₈alkenyl, —C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃,OCHF₂; provided that Q¹ is not 4-benzyloxy-2-indolyl;

Y is independently, hydrogen, —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl,halogen, oxo, aryl(optionally substituted with 1 or more R³¹ groups),hetaryl(optionally substituted with 1 or more R³¹ groups), C₀₋₆alkyl,—C₀₋₈alkylC₃₋₈cycloalkyl, —C₀₋₈alkyl-NR³¹¹S(O)₀₋₂R³²¹,—C₀₋₈alkyl-NR³¹¹S(O)₀₋₂NR³²¹R³³¹, —C₀₋₈alkyl-NR³¹¹ CO₂R³²¹,—C₀₋₈alkyl-CON(R³¹¹)S(O)₀₋₂R³²¹, —C₀₋₈alkyl-S(O)₀₋₂NR³¹¹R³²¹,—C₀₋₈alkyl-NR³¹¹COR³²¹, —C₀₋₈alkyl-NR³¹¹CONR³²¹R³³¹¹,—C₀₋₈alkyl-CONR³¹¹R³²¹, —C₀₋₈alkyl-CO₂R³¹¹, —C₀₋₈alkylS(O)₀₋₂R³¹¹,—C₀₋₈alkyl-O—C₁₋₈alkyl, —C₀₋₈alkyl-O—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-O—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-O—C₀₋₈alkylaryl,—C₀₋₈alkyl-O—C₀₋₈alkylhetaryl, —C₀₋₈alkylaryl, —C₀₋₈alkylhetaryl,—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-S—C₀₋₈alkyl,—C₀₋₈alkyl-S—-C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylaryl, —C₀₋₈alkyl-N(R³¹¹)—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-NR³¹¹R³²¹, —C₂₋₈alkenyl, —C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃,OCHF₂; provided that Q¹ is not 2-carboxy-5-benzo[b]thiophenyl;

G¹¹ is halo, oxo, —CF₃, —OCF₃, —OR³¹², —NR³¹²R³²², —C(O)R³¹²,—C(O)C₃₋₈cycloalkyl, —CO₂C₃₋₈cycloalkyl, —CO₂R³¹², —C(═O)NR³¹²R³²²,—NO₂, —CN, —S(O)₀₋₂R³¹², —SO₂NR³¹²R³²², NR³¹²(C═O)R³²², NR³¹²C(═O)OR³²²,NR³¹²C(═O)NR³²²R³³², NR³¹²S(O)₀₋₂R³²², —C(═S)OR³¹², —C(═O)SR³¹²,—NR³¹²C(═NR³²²)NR³³²R³⁴¹, —NR³¹²C(═NR³²²)OR³³², —NR³¹²C(—NR³²²)SR³³²,—OC(═O)OR³¹², —OC(═O)NR³¹²R³²², —OC(═O)SR³¹², —SC(═O)OR³¹²,—SC(═O)NR³¹²R³²², —P(O)OR³¹²OR³²², C₁₋₁₀alkylidene, C₀₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, —C₁₋₁₀alkoxyC₁₋₁₀alkyl,—C₁₋₁₀alkoxyC₂₋₁₀alkenyl, —C₁₋₁₀alkoxyC₂₋₁₀alkynyl,—C₁₋₁₀alkylthioC₁₋₁₀alkyl, —C₁₋₁₀alkylthioC₂₋₁₀alkenyl,—C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl, cycloC₃₋₈alkenyl,-cycloC₃₋₈alkylC₁₋₁₀alkyl, -cycloC₃₋₈alkenylC₁₋₁₀alkyl,-cycloC₃₋₈alkylC₂₋₁₀alkenyl, cycloC₃₋₈alkenylC₂₋₁₀alkenyl,-cycloC₃₋₈alkylC₂₋₁₀alkynyl, cycloC₃₋₈alkenylC₂₋₁₀alkynyl,-heterocyclyl-C₀₋₁₀alkyl, heterocyclyl-C₂₋₁₀alkenyl, or-heterocyclyl-C₂₋₁₀alkynyl, any of which is optionally substituted withone or more independent halo, oxo, —CF₃, —OCF₃, —OR³¹³, —NR³¹³R³²³,—C(O)R³¹³, —CO₂R³¹³, —C(═O)NR³¹³R³²³, —NO₂, —CN, —S(O)₀₋₂R³¹³,—SO₂NR³¹³R³²³, —NR³¹³C(═O)R³²³, —NR³¹³C(═O)OR³²³, —NR³¹³C(═O)NR³²³R³³³,—NR³¹³S(O)₀₋₂R³²³, —C(═S)OR³¹³, —C(═O)SR³¹³, —NR³¹³C(═NR³²³)NR³³³R³⁴²,—NR³¹³C(═NR³²³)OR³³³, —NR³¹³C(—NR³²³)SR³³³, —OC(═O)OR³³³,—OC(═O)NR³¹³R³²³, —OC(═O)SR³¹³, —SC(═O)OR³¹³, —P(O)OR³¹³OR³²³ or—SC(═O)NR³¹³R³²³ substituents;

or G¹¹ is aryl-C₀₋₁₀alkyl, aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl,hetaryl-C₀₋₁₀alkyl, hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, wherethe attachment point is from either the left or right as written, whereany of which is optionally substituted with one or more independenthalo, —CF₃, —OCF₃, —OR³¹³, —NR³¹³R³²³, —C(O)R³¹³, —CO₂R³¹³,—C(═O)NR³¹³R³²³, —NO₂, —CN, —S(O)₀₋₂R³¹³, —SO₂NR³¹³R³²³,—NR³¹³C(═O)R³²³, —NR³¹³C(═O)OR³²³, —N³¹³C(═O)NR³²³R³³³,—NR³¹³S(O)₀₋₂R³²³, —C(═S)OR³¹³, —C(═O)SR³¹³, —NR³²³C(—NR³¹³)NR³³³R³⁴²,—NR³¹³C(═NR³²³)OR³³³, —NR³¹³C(═NR³²³)SR³³³, —OC(═O)OR³¹³,—OC(═O)NR³¹³R³²³, —OC(═O)SR³¹³, —SC(═O)OR³¹³, —P(O)OR³¹³OR³²³, or—SC(═O)NR³¹³R³²³ substituents; provided that G¹¹ is not N—CH₂CO₂H whenR³ is 4-piperidinyl;

R³¹, R³², R³³, R³¹¹, R³²¹, R³³¹R³¹²R³²², R³³², R³⁴¹, R³¹³, R³²³, R³³³,and R³⁴², in each instance, is independently

-   -   C₀₋₈alkyl optionally substituted with an aryl, heterocyclyl or        hetaryl substituent, or C₀₋₈alkyl optionally substituted with        1-6 independent halo, —CON(C₀₋₈alkyl)(C₀₋₈alkyl),        —CO(C₀₋₈alkyl), —OC₀₋₈alkyl, -Oaryl, -Ohetaryl, -Oheterocyclyl,        —S(O)₀₋₂aryl, —S(O)₀₋₂hetaryl, —S(O)₀₋₂heterocyclyl,        —S(O)₀₋₂C₀₋₈alkyl, —N(C₀₋₈alkyl)(C₀₋₈alkyl),        —N(C₀₋₈alkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),        —N(C₀₋₈alkyl)CO(C₁₋₈alkyl), —N(C₀₋₈alkyl)CO(C₃₋₈cycloalkyl),        —N(C₀₋₈alkyl)CO₂(C₁₋₈alkyl), —S(O)₁₋₂N(C₀₋₈alkyl)(C₀₋₈alkyl),        —NR¹¹S(O)₁₋₂(C₀₋₈alkyl), —CON(C₃₋₈cycloalkyl)(C₃₋₈cycloalkyl),        —CON(C₀₋₈alkyl)(C₃₋₈cycloalkyl),        —N(C₃₋₈cycloalkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),        —N(C₃₋₈cycloalkyl)CON(C₃₋₈cycloalkyl)(C₀₋₈alkyl),        —N(C₀₋₈alkyl)CON(C₃₋₈cycloalkyl)(C₀₋₈alkyl),        —N(C₀₋₈alkyl)CO₂(C₃₋₈cycloalkyl),        —N(C₃₋₈cycloalkyl)CO₂(C₃₋₈cycloalkyl),        S(O)₁₋₂N(C₀₋₈alkyl)(C₃₋₈cycloalkyl)-NR¹¹S(O)₁₋₂(C₃₋₈cycloalkyl),        C₂₋₈alkenyl, C₂₋₈alkynyl, CN, CF₃, OH, or optionally substituted        aryl substituents; such that each of the above aryl,        heterocyclyl, hetaryl, alkyl or cycloalkyl groups may be        optionally, independently substituted with        —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl, halogen, oxo, aryl, hetaryl,        C₀₋₆alkyl, C₀₋₈alkylcyclyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-S(O)₀₋₂—(C₀₋₈alkyl),        C₀₋₈alkyl-S(O)₀₋₂—N(C₀₋₈alkyl)(C₀₋₈alkyl),        —C₀₋₈alkyl-N(C₀₋₈alkyl)CO(C₀₋₈alkyl),        —C₀₋₈alkyl-N(C₀₋₈alkyl)CO—N(C₀₋₈alkyl)(C₀₋₈alkyl),        C₀₋₈alkyl-CO—N(C₀₋₈alkyl)(C₀₋₈alkyl), —C₁₋₈alkyl-CO₂—C₀₋₈alkyl),        —C₀₋₈alkylS(O)₀₋₂—(C₀₋₈alkyl), —C₀₋₈alkyl-O—C₁₋₈alkyl,        —C₀₋₈alkyl-O—C₀₋₈alkylcyclyl,        —C₀₋₈alkyl-O—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-O—C₀₋₈alkylaryl,        —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-S—C₀₋₈alkyl,        —C₀₋₈alkyl-S—C₀₋₈alkylcyclyl,        —C₀₋₈alkyl-S—C₀₋₈alkylheterocyclyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,        —C₀₋₈alkyl-S—C₀₋₈alkylhetaryl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylcyclyl,        C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylheterocyclyl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylaryl,        —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylhetaryl, C₂₋₈alkenyl,        C₂₋₈alkynyl, NO₂, CN, CF₃, OCF₃, OCHF₂,        -   —C₀₋₈alkylC₃₋₈cycloalkyl,        -   —C₀₋₈alkyl-O—C₀₋₈alkyl,        -   —C₀₋₈alkyl-N(C₀₋₈alkyl)(C₀₋₈alkyl),        -   —C₀₋₈alkyl-S(O)₀₋₂—C₀₋₈alkyl, or        -   heterocyclyl optionally substituted with 14 independent            C₀₋₈alkyl, cyclyl, or substituted cyclyl substituents;

E¹ in each instance is independently halo, —CF₃, —OCF₃, —OR², —NR³¹R³²,—C(═O)R³¹, —CO₂R³¹, —CONR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹, —S(O)₀₋₂NR³¹R³²,—NR³¹C(═O)R³², —NR³¹C(═O)OR³², —NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³²,—C(═S)OR³¹, —C(═O)SR³¹, —NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³,—NR³¹C(═NR³¹)SR³¹, —OC(═O)OR³¹, —OC(═O)NR³¹R³², —OC(═O)SR³¹,—SC(═O)OR³¹, —SC(═O)N³¹R³², C₀₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,—C₁₋₁₀alkoxyC₁₋₁₀alkyl, —C₁₋₁₀alkoxyC₂₋₁₀alkenyl,—C₁₋₁₀alkoxyC₂₋₁₀alkynyl, —C₁₋₁₀alkylthioC₁₋₁₀alkyl,—C₁₋₁₀alkylthioC₂₋₁₀alkenyl, C₁₋₁₀alkylthioC₂₋₁₀alkynyl, cycloC₃₋₈alkyl,cycloC₃₋₈alkenyl, -cycloC₃₋₈alkylC₁₋₁₀alkyl,-cycloC₃₋₈alkenylC₁₋₁₀alkyl, -cycloC₃₋₈alkylC₂₋₁₀alkenyl,-cycloC₃₋₈alkenylC₂₋₁₀alkenyl, -cycloC₃₋₈alkylC₂₋₁₀alkynyl,-cycloC₃₋₈alkenylC₂₋₁₀alkynyl, -heterocyclyl-C₀₋₁₀alkyl,-heterocyclyl-C₂₋₁₀alkenyl, or -heterocyclyl-C₂₋₁₀alkynyl, any of whichis optionally substituted with one or more independent halo, oxo, —CF₃,—OCF₃, —OR³¹, —NR³¹R³², —C(═O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —NO₂, —CN,—S(═O)₀₋₂R³¹, —SO₂NR³¹, —NR³¹C(═O)R³², —NR³¹C(═O)OR³¹,—NR³¹C(═O)NR³²R³³, —NR³¹S(O)₀₋₂R³¹, —C(═S)OR³¹, —C(O)SR³¹,—NR³¹C(═NR³²)NR³³R³¹, —NR³¹C(═NR³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³¹,—OC(═O)NR³¹R³², —OC(═O)SR³¹, —SC(═O)OR³¹, or —SC(═O)NR³¹R³²substituents;

or E¹ in each instance is independently aryl-C₀₋₁₀alkyl,aryl-C₂₋₁₀alkenyl, aryl-C₂₋₁₀alkynyl, hetaryl-C₀₋₁₀alkyl,hetaryl-C₂₋₁₀alkenyl, or hetaryl-C₂₋₁₀alkynyl, where the attachmentpoint is from either the left or right as written, where any of which isoptionally substituted with one or more independent halo, —CF₃, —OCF₃,—R³¹, —NR³¹R³², —C(O)R³¹, CO₂R³¹, —C(═O)NR³¹R³², —NO₂, —CN, —S(O)₀₋₂R³¹,—S(O)₀₋₂NR³¹R³², —NR³¹C(═O)R³², —NR³¹C(═O)R³², —NR³¹C(═O)NR³²R³³,—N³¹S(O)₀₋₂R³², —C(═S)OR³¹, —C(═C)SR³¹, —NR³¹C(═NR³²)NR³³R³¹,—NR³¹C(═N³²)OR³³, —NR³¹C(═NR³²)SR³³, —OC(═O)OR³¹, —OC(═O)NR³¹R³²,—OC(═O)SR³¹, —SC(═O)OR³¹, or —SC(═O)NR³¹R³² substituents;

in the cases of —NR³¹NR³², —NR³¹¹R³²¹, —NR³¹²R³²², —NR³³²R³⁴¹,—NR³¹³R³²³, and —NR³²³R³³³, the respective R³¹ and R³², R³¹¹ and R³²¹,R³¹² and R³²², R³³¹ and R³⁴¹, R³¹³ and R³²³, and R³²³ and R³³³ areoptionally taken together with the nitrogen atom to which they areattached to form a 3-10 membered saturated or unsaturated ring; whereinsaid ring in each instance independently is optionally substituted byone or more independent —N(C₀₋₈alkyl)(C₀₋₈alkyl), hydroxyl, halogen,oxo, aryl, hetaryl, C₀₋₆alkyl, —C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)S(O)₀₋₂C₀₋₈alkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)S(O)₀₋₂N(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CO₂(C₀₋₈alkyl),—C₀₋₈alkyl-CON((C₀₋₈alkyl))S(O)₀₋₂(C₀₋₈alkyl),—C₀₋₈alkyl-S(O)₀₋₂N(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CO(C₀₋₈alkyl),—C₀₋₈alkyl-N(C₀₋₈alkyl)CON(C₀₋₈alkyl)(C₀₋₈alkyl),—C₀₋₈alkyl-CON(C₀₋₈alkyl)(C₀₋₈alkyl), —C₀₋₈alkyl-CO₂(C₀₋₈alkyl),—C₀₋₈alkylS(O)₀₋₂(C₀₋₈alkyl), —C₀₋₈alkyl-O—C₀₋₈-alkyl,—C₀₋₈alkyl-O—C₀₋₈alkylcyclyl, —C₀₋₈alkyl-O—C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-O—C₀₋₈alkylaryl, -Oaryl, —C₀₋₈alkyl-O—C₀₋₈alkylhetaryl,—C₀₋₈alkyl-S—C₀₋₈alkyl, —C₀₋₈alkyl-S—C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-S—C₀₋₈alkylheterocycloalkyl, —C₀₋₈alkyl-S—C₀₋₈alkylaryl,—C₀₋₈alkyl-S—C₀₋₈alkylhetaryl, —C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylC₃₋₈cycloalkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylheterocycloalkyl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylaryl,—C₀₋₈alkyl-N(C₀₋₈alkyl)-C₀₋₈alkylhetaryl,—C₀₋₈alkyl-N(C₀₋₈alkyl)(C₀₋₈alkyl), C₂₋₈alkenyl, C₂₋₈alkynyl, NO₂, CN,CF₃, OCF₃, or OCHF₂ substituents; wherein said ring in each instanceindependently optionally includes one or more heteroatoms other than thenitrogen;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, or 4;

aa is 0 or 1; and

provided that Formula I is not

-   trans-4-[8-amino-1-(7-chloro-4-hydroxy-1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic    acid,-   cis-3-[8-amino-1-(7-chloro-1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanecarboxylic    acid,-   trans-4-{8-amino-1-[7-(3-isopropylphenyl-1H-indol-2-yl]imidazo[1,5-a]pyrazin-3-yl}cyclohexanecarboxylic    acid or-   trans-4-{8-amino-1-[7-(2,5-dichloro)phenyl-1H-indol-2-yl]imidazo[1,5-a]pyrazin-3-yl}cyclohexanecarboxylic    acid.

According to an aspect of the present invention, the compounds arerepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ and X₇ are C; andthe other variables are as described above for Formula I.

In an embodiment of this aspect of the present invention, the compoundsare represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ and X₇are C; Q¹ is -A(R¹)_(m)B(W)_(n); and the other variables are asdescribed above for Formula I.

In another embodiment of this aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ andX₇ are C; Q¹ is —B(G¹¹)_(n)A(Y)_(m); and the other variables are asdescribed above for Formula I.

In yet another embodiment of this aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ andX₇ are C; Q¹ is optionally substituted indolyl; and the other variablesare as described above for Formula I.

In still another embodiment of this aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ andX₇ are C; Q¹ is optionally substituted benzothienyl; and the othervariables are as described above for Formula I.

In an embodiment of this aspect of the present invention, the compoundsare represented by Formula I, or a pharmaceutically acceptable saltthereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ and X₇are C; Q¹ is optionally substituted benzimidazolyl; and the othervariables are as described above for Formula I.

In another embodiment of this aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ and X₂ are CH; X₃ and X₅ are N; and X₄, X₆ andX₇ are C; Q¹ is optionally substituted benzoxazolyl; and the othervariables are as described above for Formula I.

According to a second aspect of the present invention, the compounds arerepresented by Formula I, or a pharmaceutically acceptable salt thereof,wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄, X₆ and X₇ are C; and theother variables are as described above for Formula I.

In an embodiment of the second aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄, X₆ and X₇are C; Q¹ is -A(R¹)_(m)B(W)_(n); and the other variables are asdescribed above for Formula I.

In another embodiment of the second aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄, X₆ and X₇are C; Q¹ is —B(G¹¹)_(n)A(Y)_(m); and the other variables are asdescribed above for Formula I.

In yet another embodiment of the second aspect of the present invention,the compounds are represented by Formula I, or a pharmaceuticallyacceptable salt thereof, wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄,X₆ and X₇ are C; Q¹ is optionally substituted indolyl; and the othervariables are as described above for Formula I.

In still another embodiment of the second aspect of the presentinvention, the compounds are represented by Formula I, or apharmaceutically acceptable salt thereof, wherein X₁ is CH; X₂, X₃ andX₅ are N; and X₄, X₆ and X₇ are C; Q¹ is optionally substitutedbenzimidazolyl; and the other variables are as described above farFormula I.

In another embodiment of the second aspect of the present invention, thecompounds are represented by Formula I, or a pharmaceutically acceptablesalt thereof, wherein X₁ is CH; X₂, X₃ and X₅ are N; and X₄, X₄ and X₇are C; Q¹ is optionally substituted benzoxazolyl; and the othervariables are as described above for Formula I.

In yet still another embodiment of the second aspect of the presentinvention, the compounds are represented by Formula I, or apharmaceutically acceptable salt thereof, wherein X₁ is CH; X₂, X₃ andX₅ are N; and X₄, X₆ and X₇ are C; Q¹ is optionally substitutedbenzothienyl; and the other variables are as described above for FormulaI.

The compounds of the present invention include:

or a pharmaceutically acceptable salt thereof.

The present invention includes a composition comprising a compoundaccording to Formula I, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The present invention includes a composition comprising a compoundaccording to Formula I, or a pharmaceutically acceptable salt thereof;and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemotherapeuticagent.

The present invention includes a method of treatment ofhyperproliferative disorder comprising a step of administering aneffective amount of a compound according to Formula I, or apharmaceutically acceptable salt thereof.

The present invention includes a method of treatment ofhyperproliferative disorder comprising a step of administering aneffective amount of a compound according to Formula I, or apharmaceutically acceptable salt thereof, wherein the hyperproliferativedisorder is breast cancer, lung cancer, non-small cell lung cancer,kidney cancer, renal cell carcinoma, prostate cancer, cancer of theblood, liver cancer, ovarian cancer, thyroid cancer, endometrial cancer,cancer of the GI tract, lymphoma, renal cell carcinoma, mantle celllymphoma, or endometrial cancer.

The present invention includes a method of treatment of rheumatoidarthritis, hamartoma syndromes, transplant rejection, IBD, multiplesclerosis or immunosuppression diseases comprising a step ofadministering an effective amount of the compound according to FormulaI, or a pharmaceutically acceptable salt thereof.

The present invention includes intermediates useful in making thecompounds of the invention. Such intermediates include compoundsrepresented by

or a pharmaceutically acceptable salt thereof.

In all of the above circumstances forbidden or unstable valences, N—S,N-halogen bonds are excluded.

As used herein, unless stated otherwise, “alkyl” as well as other groupshaving the prefix “alk” such as, for example, alkoxy, alkanyl, alkenyl,alkynyl, and the like, means carbon chains which may be linear orbranched or combinations thereof. Examples of alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl,hexyl, heptyl and the like. “Alkenyl”, “alkynyl” and other like termsinclude carbon chains having at least one unsaturated carbon-carbonbond.

As used herein, “C₀₋₄alkyl” for example is used to mean an alkyl having0-4 carbons—that is, 0, 1, 2, 3, or 4 carbons in a straight or branchedconfiguration. An alkyl having no carbon is hydrogen when the alkyl is aterminal group. An alkyl having no carbon is a direct bond when thealkyl is a bridging (connecting) group.

The terms “cycloalkyl”, “carbocyclic ring”, cyclic”, or “cyclyl” mean3-10 membered mono or polycyclic aromatic, partially aromatic ornon-aromatic ring carbocycles containing no heteroatoms, and includemono-, bi-, and tricyclic saturated carbocycles, as well as fused andbridged systems. Such fused ring systems can include one ring that ispartially or fully unsaturated, such as a benzene ring, to form fusedring systems, such as benzofused carbocycles. Cycloalkyl includes suchfused ring systems as spirofused ring systems. Examples of cycloalkyland carbocyclic rings include C₃₋₈cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and decahydronaphthalene,adamantane, indanyl, 1,2,3,4-tetrahydronaphthalene and the like.

The term “halogen” includes fluorine, chlorine, bromine, and iodineatoms.

The term “carbamoyl” unless specifically described otherwise means—C(O)—NH— or —NH—C(O)—.

The term “aryl” is well known to chemists. The preferred aryl groups arephenyl and naphthyl.

The term “hetaryl” is well known to chemists. The term includes 5- or6-membered heteroaryl rings containing 14 heteroatoms chosen fromoxygen, sulfur, and nitrogen in which oxygen and sulfur are not next toeach other. Examples of such heteroaryl rings are furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The term “hetaryl”includes hetaryl rings with fused carbocyclic ring systems that arepartially or fully unsaturated, such as a benzene ring, to form abenzofused hetaryl. For example, benzimidazole, benzoxazole,benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, and thelike.

Unless otherwise stated, the terms “heterocyclic ring”, “heterocycle”,“heterocyclic”, and “heterocyclyl” are equivalent, and is defined as forcyclic but also contains one or more atoms chosen independently from N,O, and S (and the N and S oxides), provided such derivatives exhibitappropriate and stable valencies. The terms include 448-memberedsaturated rings containing one or two heteroatoms chosen from oxygen,sulfur, and nitrogen. Examples of heterocyclic rings include azetidine,oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane,thiazolidine, oxazolidine, oxazetidine, pyrazolidine, isoxazolidine,isothiazolidine, tetrahydrothiophene, tetrahydrothiopyran, thiepane,thiocane, azetidine, pyrrolidine, piperidine, azepane, azocane,[1,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine,thiomorpholine, and the like. Other examples of heterocyclic ringsinclude the oxidized forms of the sulfur-containing rings. Thus,tetrahydrothiophene-1-oxide, tetrahydrothiophene-1,1-dioxide,thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide,tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide,thiazolidine-1-oxide, and thiazolidine-1,1-dioxide are also consideredto be heterocyclic rings. The term “heterocyclic” also includes fusedring systems, including het-het fused systems, and can include acarbocyclic ring that is partially or fully unsaturated, such as abenzene ring, to form benzofused heterocycles. For example,3,4-dihydro-1,4-benzodioxine, tetrahydroquinoline,tetrahydroisoquinoline, isoindoline and the like.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially pure resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art the productsof such procedures can be a mixture of stereoisomers.

The invention also encompasses a pharmaceutical composition that iscomprised of a compound of Formula I in combination with apharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of FormulaI as described above (or a pharmaceutically acceptable salt thereof.

Moreover, within this preferred embodiment, the invention encompasses apharmaceutical composition for the treatment of disease by inhibition ofmTor, comprising a pharmaceutically acceptable carrier and a non-toxictherapeutically effective amount of compound of formula I as describedabove (or a pharmaceutically acceptable salt thereof).

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium slats. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N′,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric and tartaric acids.

The pharmaceutical compositions of the present invention comprise acompound represented by formula I (or a pharmaceutically acceptable saltthereof) as an active ingredient, a pharmaceutically acceptable carrierand optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds represented by Formula I, or pharmaceuticallyacceptable salts thereof, of this invention can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical compositions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion, or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compound represented byFormula I, or a pharmaceutically acceptable salt thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

Thus, the pharmaceutical compositions of this invention may include apharmaceutically acceptable carrier and a compound or a pharmaceuticallyacceptable salt of Formula I. The compounds of Formula I, orpharmaceutically acceptable salts thereof, can also be included inpharmaceutical compositions in combination with one or more othertherapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media may be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents, and the likemay be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like may be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets may be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient.

For example, a formulation intended for the oral administration tohumans may contain from about 0.5 mg to about 5 g of active agent,compounded with an appropriate and convenient amount of carriermaterial, which may vary from about 5 to about 95 percent of the totalcomposition. Unit dosage forms will generally contain between from about1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fingi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical sue such as, for example, an aerosol, cream,ointment lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound represented byFormula I of this invention, or a pharmaceutically acceptable saltthereof, via conventional processing methods. As an example, a cream orointment is prepared by admixing hydrophilic material and water,together with about 5 wt % to about 10 wt % of the compound, to producea cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. He suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound described by Formula I, or pharmaceuticallyacceptable salts thereof, may also be prepared in powder or liquidconcentrate form.

The compounds and compositions of the present invention are useful inthe treatment of cancers of the breast lung, kidney, prostate, blood,liver, ovarian, thyroid, GI tract and lymphoma The compounds andcompositions are useful against cancers including non-small cell lungcancer (NSCLC), renal cell carcinoma, mantle cell lymphoma, andendometrial cancers. Further, the compounds and compositions are usefulin treating other indications such as rheumatoid arthritis, hamartomasyndromes, transplant rejection, irritable bowel disease (IBD), multiplesclerosis and immunosuppression.

Generally, dosage levels on the order of from about 0.01 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions, or alternatively about 0.5 mg to about 7 gper patient per day. For example, cancers of the breast, lung, kidney,prostate, blood, liver, ovarian, thyroid, GI tract and lymphoma may beeffectively treated by the administration of from about 0.01 to 50 mg ofthe compound per kilogram of body weight per day, or alternatively about0.5 mg to about 3.5 g per patient per day.

Dosage levels on the order of from about 0.01 mg/g to about 150 mg/kg ofbody weight per day are useful in the treatment of non-small cell lungcancer (NSCLC), renal cell carcinoma, mantle cell lymphoma, andendometrial cancers, or alternatively about 0.5 mg to about 7 g perpatient per day. They may be treated by the administration of from about0.01 to 50 mg of the compound per kilogram of body weight per day, oralternatively about 0.5 mg to about 3.5 g per patient per day.

Dosage levels on the order of from about 0.01 mg/kg to about 150 mg/kgof body weight per day are useful in the treatment of rheumatoidarthritis, hamartoma syndromes, transplant rejection, irritable boweldisease (IBD), multiple sclerosis and immunosuppression, oralternatively about 0.5 mg to about 7 g per patient per day. They may betreated by the administration of from about 0.01 to 50 mg of thecompound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

Biochemical Assay for Inhibition of mTOR Activity:

The ability of compounds to inhibit the mTOR kinase activity wasdetermined in an in vitro immunoprecipitation (P) kinase assay usingrecombinant 4E-BP1 as a substrate. The assay determines the ability ofcompounds to inhibit phosphorylation of 4E-BP1 a well-knownphysiological substrate of mTOR. The immunocapture mTOR complex fromHeLa cells is incubated with various concentrations of compounds andHis-tag 4E-BP1 in kinase assay buffer prior to addition of ATP to startthe reaction at RT. The reaction is stopped after 30 mins and thephosphorylated His-tag 4E-BP1 is captured on a Nickel-chelate plateovernight at 4° C. The phosphothreonine content of 4E-BP1 is thenmeasured using phospho-4E-BP1 (T37/46) primary antibody andcorresponding anti rabbit IgG IS conjugated, secondary antibody. Thesecondary antibody has a reporter enzyme (eg. horseradish peroxidase,HP) covalently attached, such that binding of primary antibody tophosphorylated 4E-BP1 can be determined quantitatively which is equal tothe amount secondary antibody bound to it. The amount of secondaryantibody can be determined by incubation with an appropriate HRPsubstrate.

The Stock Reagents Used are as Follows: Cell Lysis Buffer:

40 mM HEPES, pH 7.5 containing 120 mM NaCl, 1 mM EDTA, 10 mM sodiumpyrophosphate, 10 mM β-glycerophosphate, 50 mM sodium fluoride, 1.5 mMsodium vanadate and 0.3% CHAPS.

Complete Mini EDTA-Free Protease Inhibitors (Roche, Catalog #11 836 170001) HeLa Cell Pellets (Paragon Bioservices) Protein G Coated Plates forImmunoprecipitation (Pierce, Catalog #15131)

mTOR (aka FRAP) N-19 Antibody (Santa Cruz Biotechnology, Catalog#sc-1549)

IP Wash Buffer:

50 mM HEPES, pH 7.5 containing 150 mM NaCl

Kinase Buffer:

20 mM HEPES, pH 7.5 containing 10 mM MgCl2, 4 mM MnCl2, 10 mM bmercaptoethanol and 200 uM sodium vanadate. Make fresh for assay.

Recombinant 4E-BP1 (aka PHAS I) (Calbiochem, Catalog #516675)

Dilute 4E-BP1 stock (1 mg/mL) 120 times in kinase assay buffer to obtaina concentration of 0.25 ug/well in 30 uL

ATP Solution

Prepare 330 uM ATP stock In kinase buffer

Ni-Chelate Plate (Pierce, Catalog #15242) Antibody Dilution Buffer:

TBST containing 5% skin milk

Phospho-4E-BP1 (T37/46) Antibody:

1:1000 dilution of phospho-4E-BP1 (T37/46) antibody (Cell SignalingTechnology, catalog #9459) in antibody dilution buffer

Donkey Anti Rabbit IgG, HRP Conjugated

1:10,000 dilution of anti rabbit IgG HRP conjugated (GE Healthcare,Catalog# NA934) in antibody dilution buffer

HRP Substrate:

Chemiluminescent reagents (Pierce, catalog# 37074)

Assay Protocol:

HeLa cell lysate was prepared in bulk by homogenizing 25 g of cellpellet in 60 mL of cell lysis buffer and then, centrifuged at 12,000 rpmfor 30 min. The clear supernatant was transferred to fresh tube,aliquoted, quickly frozen and stored at −80° C. until use.

Protein G coated 96-well plate is washed once with lysis buffer and 50μL of diluted mTOR antibody is added to each well, and incubated at RTfor 30-60 min. Then, 50 μg of HeLa cell lysate was added to each well in50 μL of lysis buffer and incubated at 4° C. in a cold room on a shakerfor 2-3 h. Lysate was removed and the plate was washed with 100 μL ofcomplete lysis buffer for 3 times. The plate was further washed 2 timeswith 100 μL of high salt wash buffer. Diluted 4E-BP1 (substrate) isadded to each well in 30 μL. The compounds were added in variousconcentrations in 5 μL to each well. The drug concentrations varied from30 μM to 0.1 μM. The final DMSO concentration was 1%. Only DMSO wasadded to positive control wells. For negative control wells, no ATPsolution was added but instead 15 μL of kinase buffer was added, thereaction was started by addition of ATP in 15 μL to a finalconcentration of 100 μM to rest of the wells except negative controlwells. The reaction was carried out for 30 min at RT. Then, 45 μL of thereaction mixture was transferred to Ni-chelate plate and incubatedovernight at 4° C. The plate was washed once with antibody dilutionbuffer and 50 μL of diluted phospho-4E-BP1 antibody was added to eachwell, and incubated at RT for 1 h. Then, the plate was washed 4 timeswith TBST and 50 uL of diluted anti-rabbit secondary antibody was addedto each plate, and incubated at RT for 1 h. The plate was washed 4 timeswith 100 μL of TBST. To each well, 50 μL, of Pierce Femtochemiluminescent reagent was added and the chemiluminescence wasmeasured using victor machine.

Comparison of the assay signals obtained in the presence of compoundwith those of positive and negative controls, allows the degree ofinhibition of phospho-4E-BP1 phosphorylation to be determined over arange of compound concentrations. These inhibition values were fitted toa sigmoidal dose-response inhibition curve to determine the IC₅₀ values(i.e. the concentration of the compound that inhibits phosphorylation of4E-BP1 by 50%).

mTOR Cell-Based Mechanistic Assay to Measure the Inhibition ofPhosphorylation of 4E-BP1 (T37/46)

MDA-MB-231 cells were plated in 96 well plates at 2×10⁴ cells/well in 90ul of complete growth medium and incubated at 37° C. O/N in a CO₂incubator. Cells were treated with various compounds in a dose responsemanner for 3 h at 37° C. in a CO₂ incubator before making cell lysatesto measure inhibition of phosphorylation of 4E-BP1 at T37/46. Celllysates were transferred to a 96-well plate coated with 4E-BP1antibodies to capture phospho-4E-BP1 (T37/46) and incubated O/N at 4° C.The amount of phospho-4E-BP1 in each well is further measured byincubating the wells with anti-rabbit phospho-4E-BP1 (T37146) antibodiesand a corresponding goat anti-rabbit IgG conjugated to HRP. Amount ofHRP present in each well is measured by a chemiluminescence method,which corresponds to amount of phospho-4E-BP in each well. IC₅₀ valueswere determined using a 6-point dose response curve.

Biochemical Assay for Inhibition of IGF-1R Activity:

IGF-1R inhibition was shown in a tyrosine kinase assay using purifiedGST fusion protein containing the cytoplasmic kinase domain of humanIGF-1R expressed in Sf9 cells. This assay is carried out in a finalvolume of 90 μL containing 1-100 nM (depending on the specific activity)in an Immulon-4 96-well plate (Thermo Labsystems) pre-coated with 1Swell of substrate poly-glu-tyr (4:1 ratio) in kinase buffer (50 mMHepes, pH 7.4, 125 mM NaCl, 24 mM MgCl₂, mM MnCl₂, 1% glycerol, 200 μMNa₃VO₄, and 2 mM DTT). The enzymatic reaction was initiated by additionof ATP at a final concentration of 100 μM. After incubation at roomtemperature for 30 minutes, the plates were washed with 2 mM Imidazolebuffered saline with 0.02% Tween-20. Then the plate was incubated withanti-phosphotyrosine mouse monoclonal antibody pY-20 conjugated withhorse radish peroxidase (HRP) (Calbiochem) at 167 ng/mL diluted inphosphate buffered saline (PBS) containing 3% bovine serum albumin(BSA), 0.5% Tween-20 and 200 μM Na₃VO₄ for 2 hours at room temperature.Following 3× 250 μL washes, the bound anti-phosphotyrosine antibody wasdetected by incubation with 100 μl/well ABTS (Kirkegaard & Perry Labs,Inc.) for 30 minutes at room temperature. The reaction was stopped bythe addition of 100 μl/well 1% SDS, and the phosphotyrosine dependentsignal was measured by a plate reader at 4051490 nm.

The EXAMPLES of this invention demonstrated at least one of thefollowing:

I) Inhibited phosphorylation of 4E-BP1 by immunocaptured human mTOR asdetermined in the Biochemical Assay for Inhibition of mTOR Activity withIC₅₀ values between 0.001 μM and 11.00 μM. It is advantageous that theIC₅₀ values be less than 1.00 μM and more advantageous that the IC₅₀values be below 0.1 μM. Even more advantageous, the IC₅₀ values be lessthan 0.01 μM.

II) Inhibited the phosphorylation of 4E-BP1 (T37/46) in the mTORCell-based Mechanistic Assay with IC₅₀ values below 40 μM.

III) Inhibition of IGF-1R in the Biochemical Assay for Inhibition ofIGF-1R Activity with IC₅₀ values less than 15 μM.

EXPERIMENTAL

The following schemes, intermediates and examples serve to demonstratehow to synthesize compounds of this invention, but in no way limit theinvention. Additionally, the following abbreviations are used: Me formethyl, Et for ethyl, iPr or iPr for isopropyl, n-Bu for n-butyl, t-Bufor tert-butyl, Ac for acetyl, Ph for phenyl, 4Cl-Ph or (4Cl)Ph for4-chlorophenyl, 4Me-Ph or (4Me)Ph for 4-methylphenyl, p-CH3O)Ph forp-methoxyphenyl, (p-NO2)Ph for p-nitrophenyl, 4Br-Ph or (4Br)Ph for4-bromophenyl, 2-CF3-Ph or (2CF3)Ph for 2-trifluoromethylphenyl, DMAPfor 4-(dimethylamino)pyridine, DCC for 1,3-dicyclohexylcarbodiimide, EDCfor 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBtfor 1-hydroxybenzotriazole, HOAt for 1-hydroxy-7-azabenzotriazole, TMPfor tetramethylpiperidine, n-BuLi for n-butyllithium, CDI for1,1′-carbonyldiimidazole, DEAD for diethyl azodicarboxylate, PS-PPh3 forpolystyrene triphenylphosphine, DIEA for diisopropylethylamine, DIAD fordiisopropyl azodicarboxylate, DBAD for di-tert-butyl azodicarboxylate,HPFC for high performance flash chromatography, rt or RT for roomtemperature, min for minute, h for hour, Bn for benzyl, and LAH forlithium aluminum hydride.

Accordingly, the following are compounds that are useful asintermediates in the formation of mTOR inhibiting EXAMPLES.

The compounds of Formula I of this invention and the intermediates usedin the synthesis of the compounds of this invention were preparedaccording to the following methods. Method A was used when preparingcompounds of Formula I-AA

as shown below in Scheme 1:

Method A:

where Q¹ and R³ are as defined previously for compound of Formula I.

In a typical preparation of compounds of Formula I-AA, compound ofFormula II was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvents were isopropanol and a mixture of THFand isopropanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 80° C. and about 120° C. The above process toproduce compounds of the present invention was preferably carried in asealed reaction vessel such as but not limited to a thick walled glassreaction vessel or a stainless steel Parr bomb. An excess amount of thereactant ammonia, was preferably used.

The compounds of Formula II of Scheme 1 were prepared as shown below inScheme 2.

where Q¹ and R³ are as defined previously for compound of Formula I.

In a typical preparation of a compound of Formula II, an intermediate ofFormula III was treated with POCl₃ or the isolated “Vilsmeier salt”[CAS# 33842-02-3] in a suitable solvent at a suitable reactiontemperature. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like; acetonitrile; and chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used or no solvent was used. The preferred solventsincluded methylene chloride and acetonitrile. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 20° C. and about 95° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III of Scheme 2 were prepared as shown below inScheme 3:

where Q¹ and R¹ are as defined previously for compound of Formula I andA¹=OH, alkoxy, or a leaving group such as a halogen or imidazole.

In a typical preparation, of a compound of Formula III, a compound ofFormula IV and compound of Formula V were reacted under suitable amidecoupling conditions. Suitable conditions include but are not limited totreating compounds of Formula IV and V (when A¹=OH) with couplingreagents such as DCC or EDC in conjunction with DMAP, HOAt, HOAt and thelike. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride. Ifdesired, mixtures of these solvents were used, however the preferredsolvents were methylene chloride and DMF. The above process was carriedout at temperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about rt. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Alternatively, compounds of Formula IV and V (where A¹=F, Cl, Br, I)were reacted with bases such as triethylamine or ethyldiisopropylamineand the like in conjunction with DMAP and the like. Suitable solventsfor use in this process included, but were not limited to, ethers suchas tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such aschloroform or methylene chloride. If desired, mixtures of these solventswere used, however the preferred solvent was methylene chloride. Theabove process was carried out at temperatures between about −20° C. andabout 40° C. Preferably, the reaction was carried out between 0° C. and25° C. The above process to produce compounds of the present inventionwas preferably carried out at about atmospheric pressure although higheror lower pressures were used if desired. Substantially equimolar amountsof compounds of Formula IV and V (where A¹=F, Cl, Br, I) and base andsubstoichiometric amounts of DMAP were preferably used although higheror lower amounts were used if desired. Additionally, other suitablereaction conditions for the conversion of a compound of Formula IV to acompound of Formula III can be found in Larock, R. C. ComprehensiveOrganic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp1941-1949.

The compounds of Formula IV of Scheme 3 were prepared as shown below inScheme 4:

where Q¹ is as defined previously for compound of Formula I andA²=phthalimido or N₃.

In a typical preparation, of a compound of Formula IV, a compound ofFormula VI is reacted under suitable reaction conditions in a suitablesolvent. When A²=phthalimido, suitable conditions include treatment ofcompound of Formula VI with hydrazine in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvent was ethanol. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. In the transformation of compound of Formula VI to IV,if A²═N₃, then one skilled in the art would recognize that typical azidereduction conditions could be employed, including but not limited toPPh₃ and water or hydrogenation in the presence of a metal catalyst suchas palladium.

The compounds of Formula VI of Scheme 4 were prepared as shown below inScheme 5.

where Q¹ is as defined previously for compound of Formula I andA²=phthalimido or N₃.

In a typical preparation of a compound of Formula VI (whenA²=phthalimido), a compound of Formula VII was reacted with aphthalimide under typical Mitsunobu conditions in a suitable solvent inthe presence of suitable reactants. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (MD),dimethyl sulfoxide (DMSO); acetonitrile (CH₃CN); chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent wasTHF. Suitable reactants for use in the above process included, but werenot limited to, triphenylphosphine and the like, and an azodicarboxylateDIAD, DEAD, DBAD). The preferred reactants were triphenylphosphine orresin-bound triphenylphosphine (PS-PPh₃), and DIAD. The above processmay be carried out at temperatures between about −78° C. and about 10°C. Preferably, the reaction was carried out at about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Generally, one equivalent or a slight excess, 1.1equivalents, of triphenylphosphine, DIAD and phthalimide was used perequivalent of compound of Formula VII. Additionally, compound of FormulaVII can be reacted with Ts₂O, Ms₂O, Tf₂O, TsCl, MsCl, or SOCl₂ in whichthe hydroxy group is converted to a leaving group such as its respectivetosylate, mesylate, triflate, or halogen such as chloro and subsequentlyreacted with an amine equivalent such as NH(Boc)₂, phthalimide,potassium phthalimide, or sodium azide. Conversion of the amineequivalents by known methods such as by treating under acidic conditions(NH(Boc)₂), with hydrazine (phthalimide) as shown in Scheme 4, or withtriphenylphosphine/water (azide) will afford the desired amine as shownin Scheme 4.

The compounds of Formula VII of Scheme 5 were prepared from aldehydesQ¹-CHO and a 2-chloropyrazine VIII as shown below in Scheme 6:

where Q¹ is as defined previously for compound of Formula I.

In a typical preparation, of a compound of Formula VI, a compound ofFormula VIII was reacted under suitable reaction conditions in asuitable solvent with a compound of Formula Q¹-CHO. Suitable conditionsincluded but were not limited to treating compounds of Formula VIII witha base such as lithium tetramethylpiperidide (Li-TMP) followed bytreating with compounds of Formula Q¹-CHO. Lithium tetramethylpiperididemay be prepared by reacting tetramethylpiperidine with n-butyllithium at−78° C. and warming up to 0° C. Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like. Polar solvents such ashexamethylphosphoramide (HMPA),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMPU), and the likemay be added if necessary. If desired, mixtures of these solvents wereused, however, the preferred solvent was THF. The above process may becarried out at temperatures between about −80° C. and about 20° C.Preferably, the reaction was carried out at −78° C. to 0° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula I of this invention and the intermediates usedin the synthesis of the compounds of this invention were also preparedaccording to the following methods. Method AA was used when preparingcompounds of Formula I-AA from compound of Formula I-AAA as shown belowin Scheme 7:

Method AA:

where Q¹ and R³ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I and B(OR)₂=suitable boronic acid/ester.

In a typical preparation of compounds of Formula I-AA, compound ofFormula I-AAA was reacted with a suitable boronic acid/ester (Q¹-B(OR)₂)in a suitable solvent via typical Suzuki coupling procedures. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, dioxane, dimethoxyethane,and the like; dimethylformamide (DMF); dimethyl sulfoxide DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent wasdimethoxyethane/water. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 60° C. and about 100° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Substantially equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of Formula I-AA from I-AAA. Forexample, compound of Formula I-AAA could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula I-AAA of Scheme 7 were prepared as shown belowin Scheme 8.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula I-AAA, compound ofFormula II-Z was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvents were isopropanol and a mixture of THFand isopropanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 80° C. and about 120° C. The above process toproduce compounds of the present invention was preferably carried in asealed reaction vessel such as but not limited to a thick walled glassreaction vessel or a stainless steel Parr bomb. An excess amount of thereactant, ammonia, was preferably used.

The compounds of Formula II-Z of Scheme 8 were prepared as shown belowin Scheme 9.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula II-Z, intermediateIII-Z was converted to compound of Formula II-Z′. Intermediate ofFormula III-Z was treated with POCl₃ in a suitable solvent at a suitablereaction temperature. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THY),glyme, and the like; acetonitrile; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used. The preferred solvents included methylenechloride and acetonitrile. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 20° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. In the conversion of compound of Formula III-Z toII-Z′, suitable halogenating agent were used, but were not limited to,Br₂, I₂, Cl₂, N-chlorosuccinimide, N-bromosuccinimide, orN-iodosuccinimide. The preferred halogenating agent wasN-iodosuccinimide. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent was DMF. Theabove process was carried out at temperatures between about −78° C. andabout 120° C. Preferably, the reaction was carried out between 40° C.and about 75° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts were used if desired.

The compounds of Formula III-Z of Scheme 9 were prepared as shown belowin Scheme 10:

where R³ is as defined previously for compound of Formula I and A¹=OH,alkoxy, or a leaving group such as chloro or imidazole.

In a typical preparation, of a compound of Formula III-Z a compound ofFormula IV-Z and compound of Formula V were reacted under suitable amidecoupling conditions. Suitable conditions include but are not limited totreating compounds of Formula IV-Z and V (when A¹=OH) with couplingreagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt and thelike. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride. Ifdesired, mixtures of these solvents were used, however the preferredsolvent was methylene chloride. The above process was carried out attemperatures between about 0° C. and about 80° C. Preferably, thereaction was carried out at about 22° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.Additionally, if compound of Formula IV-Z was a salt or bis-salt, asuitable base was required and included, but was not limited to,diisopropylethylamine or triethylamine. Alternatively, compounds ofFormula IV-Z and V (where A¹=F, Cl, Br, D) were reacted with bases suchas triethylamine or ethyldiisopropylamine and the like in conjunctionwith DMAP and the like. Suitable solvents for use in this processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; halogenated solvents such as chloroform or methylenechloride. If desired, mixtures of these solvents were used, however thepreferred solvent was methylene chloride. The above process was carriedout at temperatures between about −20° C. and about 40° C. Preferably,the reaction was carried out between 0° C. and 25° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially equimolar amounts of compounds of FormulaIV-Z and V (where A¹=F, Cl, Br, I) and base and substoichiometricamounts of DMAP were preferably used although higher or lower amountswere used if desired. Additionally, other suitable reaction conditionsfor the conversion of an amine (compound of Formula IV-Z) to an amide(compound of Formula III-Z) can be found in Larock, R. C. ComprehensiveOrganic Transformations, 2nd ed.; Wiley and Sons: New York, 1999, pp1941-1949.

The compounds of Formula IV-Z of Scheme 10 were prepared as shown belowin Scheme 11:

where A² is phthalimido or N₃.

In a typical preparation, of a compound of Formula IV-Z, a compound ofFormula VI-Z is reacted under suitable reaction conditions in a suitablesolvent. When A²=phthalimido, suitable conditions include treatment ofcompound of Formula VI-Z with hydrazine in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvent was ethanol. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula VI-Z of Scheme 11 were prepared as shown belowin Scheme 12:

where A²=phthalimido or N₃.

In a typical preparation of a compound of Formula VI-Z (whenA²=phthalimido), a compound of Formula VII-Z was reacted with aphthalimide under typical Mitsunobu conditions in a suitable solvent inthe presence of suitable reactants. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile (CH₃CN); chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent wasTHF. Suitable reactants for use in the above process included, but werenot limited to, triphenylphosphine and the like, and an azodicarboxylate(DIAD, DEAD, DBAD). The preferred reactants were triphenylphosphine orresin-bound triphenylphosphine (PS-PPh₃) and DIAD. The above process maybe carried out at temperatures between about −78° C. and about 100° C.Preferably, the reaction was carried out at about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Generally, 1.0 or 1.1 equivalents oftriphenylphosphine, DIAD and phthalimide was used per equivalent ofcompound of Formula VII-Z. Additionally, compound of Formula VII-Z canbe reacted with Ts₂O, Ms₂O, Tf₂O, TsCl, MsCl, or SOCl₂ in which thehydroxy group is converted to a leaving group such as its respectivetosylate, mesylate, triflate, or halogen such as chloro and subsequentlyreacted with an amine equivalent such as NH(Boc)₂, phthalimide,potassium phthalimide or sodium azide. Conversion of the amineequivalents by known methods such as by treating under acidic conditions(NH(Boc)), with hydrazine phthalimide) as shown in Scheme 4, or withtriphenylphosphine/water (azide) will afford the desired amine as shownin Scheme 4.

The compounds of Formula VI-Z of Scheme 12 were prepared from2-chloropyrazine VIII as shown below in Scheme 13:

In a typical preparation, of a compound of Formula VII-Z, a compound ofFormula VIII was reacted under suitable reaction conditions in asuitable solvent. Suitable reaction conditions included, but were notlimited to, treating compounds of Formula VIII with a base such aslithium tetramethylpiperidide (Li-TMP) followed by treatment with areagent containing a carbonyl equivalent followed by treatment with asuitable reducing agent. Lithium tetramethylpiperidide may be preparedby reacting tetramethylpiperidine with n-butyllithium at −78° C. andwarming up to 0° C. Suitable solvents for use in the above processincluded, but were not limited to, ethers such as tetrahydrofuran (THF),glyme, and the like. Polar solvents such as hexamethylphosphoramide(HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), andthe like may be added if necessary. If desired, mixtures of thesesolvents were used, however, the preferred solvent was THF. Suitablecarbonyl equivalent reagents include, but are not limited to, formamidessuch as DMF or suitable chloroformate such as methyl or ethylchloroformate. After addition of the suitable carbonyl equivalentreagent, the reaction if charged with a polar protic solvent such as,but not limited to, methanol or ethanol followed by treatment with asuitable reducing agent such as sodium borohydride. The above processmay be carried out at temperatures between about −80° C. and about 20°C. Preferably, the reaction was carried out at −78° C. to 0° C. Theabove process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula X-Z (Q¹-CHO) of Scheme 6 were prepared as shownbelow in Scheme 14:

where Q1 is as defined previously for compound of Formula I.

In a typical preparation, of a compound of Formula X-Z (Q¹-HO), acompound of Formula IX-Z (Q¹-CH₃) was reacted with a suitable oxidizingagent under suitable reaction conditions. Suitable oxidizing agentsincluded, but were not limited to, selenium dioxide. Suitable reactionconditions for use in the above process included, but were not limitedto, heating a mixture of selenium dioxide and compounds of Formula IX-Z(Q¹-CH₃) neat or in a suitable solvent such as, but not limited to,chlorobenzene or sulpholane. The above process may be carried out attemperatures between about 120° C. and about 180° C. Preferably, thereaction was carried out at 150° C. to 165° C. The above process toproduce compounds of the present invention was preferably carried out atabout atmospheric pressure although higher or lower pressures were usedif desired. Preferably, 1-1.5 eq. selenium dioxide were used althoughhigher or lower amounts were used if desired. Alternatively, a compoundof Formula IX-Z (Q¹-CH₃) was reacted first with a halogenating agent anda radical initiator under suitable reaction conditions in a suitablesolvent to give a compound of Formula Q¹-CH₂Hal (wherein Hal=Cl or Br)that was then further reacted with DMSO and a base under suitablereaction conditions to give a compound of Formula X-Z (Q¹-CHO). Suitablehalogenating agents included, but were not limited to, bromine,N-bromosuccinimide, and chlorine. Preferably, N-bromosuccinimide wasused. Suitable radical initiators included, but were not limited to,2,2′-azobisisobutyronitrile (AIBN) and UV light. Preferably, AIBN wasused. Preferably, carbon tetrachloride was used as solvent for thehalogenation step, although other halogenated solvents may be added. Thehalogenation may be carried out at temperatures between about 60° C. andabout 10° C. Preferably, the reaction was carried out at about 80° C.Suitable bases included, but were not limited to, sodiumhydrogencarbonate, sodium dihydrogenphosphate, disodiumhydrogenphosphate, and collidine. Preferably, sodium hydrogencarbonatewas used. DMSO was preferably used as solvent although other solventsmay be added. The second step may be carried out at temperatures betweenabout 40° C. and about 140° C. Preferably, the reaction was carried outat about 90° C. Additionally, other suitable reaction conditions for theconversion of Q¹-CH₃ to Q¹-CHO can be found in Larock, R. C.Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: NewYork, 1999, pp 1205-1207 and 1222-1224.

The compounds of Formula XIV-Z (Q¹-B(OR)₂) of Scheme 7 were prepared asshown below in Scheme 15:

where Q¹ is as defined previously for compound of Formula I, A¹¹¹=OTf orhalogen such as Cl, Br, or I and B(OR)₂=suitable boronic acid/ester.

In a typical preparation, of a compound of Formula XIV-Z (Q¹-B(OR)₂), acompound of Formula XIII-Z (Q¹-A¹¹¹) was reacted with a suitable metalcatalyst and a suitable boronating agent under suitable reactionconditions. Suitable metal catalyst agents included, but were notlimited to, Pd(OAc)₂ in the presence of1,3-bis(2,6-diisopropylphenyl)imidazolium chloride. Suitable boronatingagents included, but were not limited to, bis(pinacolato)diboron.Suitable reaction conditions for use in the above process included, butwere not limited to, heating a mixture of Pd(OAc)₂,1,3-bis(2,6-diisopropylphenyl)imidazolium chloride, KOAc, andbis(pinacol)borane in a suitable solvent such as, but not limited to,THF. The above process may be carried out at temperatures between about20° C. and about 100° C. Preferably, the reaction was carried out at 60°C. to 80° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Preferably, 2-3eq. KOAc, 1-1.5 eq. bis(pinacol)borane, 0.03-1 eq. Pd(OAc)₂, and 0.09-3eq. 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride were usedalthough higher or lower amounts were used if desired. Additionally,other suitable reaction conditions for the conversion of Q¹-A¹¹¹ toQ¹-B(OR)₂ can be found in the literature which involve a variety ofQ¹-A¹¹¹ or aryl/heteroarylhalides and a variety of conditions (Biooganic& Medicinal Chemistry Letters, 2003, 12(22), 4001; Biooganic & MedicinalChemistry Letters, 2003, 13(18), 3059; Chemical Communications(Cambridge, UK), 2003, 23, 2924; Synthesis, 2002, 17, 2503; AngewandteChemie, International Ed., 2002, 41(16), 3056; Journal of the AmericanChemical Society, 2002, 124(3), 390; Organic Letters, 2002, 4(4), 541;Tetrahedron, 2001, 57(49), 9813; Journal of Organic Chemistry, 2000,65(1), 164; Journal of Organic Chemistry, 1997, 62(19), 6458; Journal ofOrganometallic Chemistry, 1983, 259(3), 269). In some cases, compoundsof Formula XIII-Z (Q¹-A¹¹¹) and XIV-Z (Q¹-B(OR)₂) are commerciallyavailable or synthesized according to literature procedures. In caseswhere neither are available, compounds of Formula XIII-Z (Q¹-A¹¹¹) andXIV-Z (Q¹-B(OR)₂) were synthesized via procedures described in theexperimental section herein.

Both R³ and Q¹ in the compounds described herein in some instancescontain functional groups that can be further manipulated. It would beappreciated by those skilled in the art that such manipulation offunctional groups can be accomplished with key intermediates or withlate stage compounds. Such functional group transformations areexemplified in the following Schemes 16-26 as well as in theexperimental section but are in no way meant to limit the scope of suchtransformations. Additionally, the chemistry shown in Schemes 1626 canalso be applied to compounds of I-AAA, II-Z, and II-Z′.

The compounds of Formula I-A (compounds of Formula I-AA whereR³=Z-CONR³¹²R³²²) were prepared as shown below in Scheme 17.

where Q¹, R³¹² and R³²² are as defined previously for compound ofFormula I and A³=hydrogen or alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-A, when A³=alkyl andR³¹² and R³²² were both equal to H, reaction of compound of Formula II-A(compounds of Formula II where R³=Z—CO₂A³) with ammonia in a suitablesolvent, afforded compound of Formula I-A. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvents were isopropanol and a mixture of isopropanol/THF. The aboveprocess was carried out at temperatures between about −78° C. and about120° C. Preferably, the reaction was carried out between 80° C. andabout 120° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts were used if desired. Additionally, in a typicalpreparation of compound of Formula I-A, compound of Formula II-A (whenA³=H) was reacted with HNR³¹²R³²² followed by ammonia in a suitablesolvent. When A³=H, typical coupling procedures as described in Scheme 3(conversion of CO₂H to COCl via treatment with SOCl₂ or oxalyl chloridefollowed by reaction with HR³¹²R³²² or treatment of CO₂H and HR³¹²R³²²with EDC or DCC in conjunction with DMAP, HOBT, or HOAt and the like)were employed to afford the transformation of a carboxylic acid to anamide. When A³=alkyl such as methyl or ethyl, treatment of the esterwith Al(NR³¹²R³²²) afforded conversion of CO₂A³ to CO(NR³¹²R³²²).Subsequent treatment with ammonia afforded compounds of Formula I-A.

The compounds of Formula I-A′ (compounds of Formula I-AA where R³═CO₂A³)and I-A″ (compounds of Formula I-AA where R³=Z-CO₂H were prepared asshown below in Scheme 17:

where Q¹ is as defined previously for compounds of Formula I andA³=alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-A′, compound ofFormula II-A was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (TH-F), glyme, and the like;dimethylformamide DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 100° C. and about 120°C. The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. In most cases, the reactions wererun in a sealed tube. Substantially equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.Typically, an excess of ammonia was used and the reaction was monitoredin order to ensure that additional of ammonia to the ester moiety didnot occur to an appreciable extent. Additionally, in a typicalpreparation of compound of Formula I-A″, compound of Formula I-A′ wasreacted under typical saponification conditions such as NaOH inTHF/H₂O/MeOH. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent was amixture of THF/H₂O/MeOH. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between rt and about 60° C. The above processto produce compounds of the present invention was preferably carried outat about atmospheric pressure although higher or lower pressures wereused if desired. Substantially equimolar amounts of reactants werepreferably used although higher or lower amounts were used if desired.

The compounds of Formula II-B (compounds of Formula II where R³=Z-CH₂OH)and I-B (compounds of Formula I-AA where R³=Z-CH₂OH) were prepared asshown below in Scheme 18:

where Q¹ is as defined previously for compound of Formula I andA³=hydrogen or alkyl such as methyl or ethyl.

In a typical preparation of compound of Formula I-B, compound of FormulaII-A is treated with a suitable reducing agent such as lithium aluminumhydride in a suitable solvent, such as THF to afford compound of FormulaII-B. Suitable solvents for use in the above process included, but werenot limited to, ethers such as tetrahydrofuran (THF), glyme, and thelike; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used.The preferred solvent was THF. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 0° C. and about 50° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Subsequent treatment of compound of Formula II-B underpreviously described ammonolysis conditions (ammonia in isopropanol in asealed tube at 120° C.), afforded compound of Formula I-B.

The compounds of Formula II-C (compounds of Formula II whereR³=Z-CH₂A⁴), II-D (compounds of Formula II whereR³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)), I-B (compounds of Formula I-AA whereR³=Z-CH₂OH) and I-C (compounds of Formula I-AA whereR³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)) were prepared as shown below in Scheme 19:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I, A⁴=suitable leaving group such as OTs, OMs, OTf, or halo suchas chloro, bromo, or iodo; d=0 or 1; and A⁵=N, O or S.

In a typical preparation of compound of Formula I-C, the hydroxy groupof compound of Formula II-B was converted to a suitable leaving group,A⁴, such as Cl or OTs, OMs, or OTf, by reaction with SOCl₂ or Ts₂O,Ms₂O, or Tf₂O to afford compound of Formula II-C. Reaction of compoundof Formula II-C with HA⁵(R³¹³)(R³²³)_(aa) afforded compound of FormulaII-D. Subsequent reaction of compound of Formula II-D) under previouslydescribed ammonolysis conditions afforded compound of Formula I-C.Additionally, compound of Formula II-B was converted to compound ofFormula I-B as described previously in Scheme 18. Further conversion ofcompound of Formula I-B to compound of Formula I-C was accomplished byfollowing the previously described conditions for the conversion ofcompound of Formula II-B to compound of Formula II-C and the furtherconversion of compound of Formula II-C to compound of Formula II-D (inthe net conversion of OH to A⁵(R³¹³)(R³²³)_(aa)). Furthermore, compoundof Formula II-B can be directly converted to compound of Formula II-D bytreating compound of Formula II-B with various alkylating agent or withphenols via the Mitsunobu reaction to afford compounds Formula II-D(compounds of Formula II where R³═CH₂-Z-A⁵(1R³¹³)(R³²³)_(aa)) in whichA⁵=O, aa=0, and R³¹³=alkyl or aryl).

The compounds of Formula I-C′ (compounds of Formula I-AA whereR³=Z-CH₂-A²), I-C″ (compounds of Formula I-AA where R³=Z-CH₂—NH₂), andI-C′″ (compounds of Formula I-AA where R³=Z-CH₂—N(R³¹³)(R³²³)) wereprepared as shown below in Scheme 20:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I and A²=phthalimido or N₃.

In a typical preparation of compounds of Formula I-C′, I-C″, and I-C′″,the hydroxy group of compound of Formula I-B was converted to A²,following the procedures as described in Scheme 5 for the conversion ofcompound of Formula VII to compound of Formula VI. Reaction of compoundof Formula I-C′ under conditions described in Scheme 4 afforded compoundof Formula I-C″C″. Reaction of compound of Formula I-C″ with, but notlimited to various alkylating agents, various aldehydes/ketones underreductive amination conditions, various acylating agents such as aceticanhydride, benzoyl chlorides, or with carboxylic acids in the presenceof EDC or DCC with HOBT or HOAT, or with sulphonylating agents such asTs₂O or MeSO₂Cl afforded compounds of Formula I-C′″. For example, in atypical preparation of compounds of Formula I-C′″, a compound of FormulaI-C″ is treated with a suitable acylating agent in the presence of asuitable base in a suitable solvent. Suitable solvents for use in theabove process included, but were not limited to, ethers such astetrahydrofuran (IMP), glyme, and the like; and chlorinated solventssuch as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired,mixtures of these solvents were used, however, the preferred solvent waschloroform. Suitable bases for use in the above process included, butwere not limited to, trialkylamines such as diisopropylethylamine,triethylamine, or resin bound trialkylamines such as PS-DIEA. Thepreferred base was PS-DIEA. In the case where the suitable acylatingagent was acetic anhydride, the conversion of compound of Formula I-C″to compound of Formula I-C′″ where R³¹³═H and R³²³═COCH₃ wasaccomplished. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 0° C. and about 20° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired.

The compounds of Formula I-D (compounds of Formula I-AA whereR³═(CH₂)_(n)-Z²-H and Z² is a heterocyclyl ring containing a nitrogenatom connected to H) and I-E (compounds of Formula I-AA whereR³═(CH₂)_(n)-Z²-R³¹ and Z² is a heterocyclyl ring containing a nitrogenatom connected to R³¹) were prepared as shown below in Scheme 21:

where Q¹ and R³¹ are as defined previously for compound of Formula I,G^(99a) is C(═O)A⁶ or CO₂A⁶, n=0-5, and A⁶=alkyl, aryl, or aralkyl.

In a typical preparation of compound of Formula I-E, compound of FormulaII-E is treated with suitable reagents capable of converting N-G^(99a)to N—H and therefore afford compound of Formula I-D. For example,treatment of compound of Formula II-E (when G^(99a) is equal to CO₂Bn)under previously described ammonolysis conditions followed by treatmentwith concentrated HCl and a suitable basic workup, affords compound ofFormula I-D. Compound of Formula I-D can be subjected to variousconditions including but not limited to reductive aminations, alkationsand ar(hetar)ylations, and acylations to afford amides, ureas,guanidines, carbamates, thiocarbamates, sulphonamides, and variouslysubstituted nitrogen adducts to afford the net conversion of NH to NR².

The compounds of Formula II-G (compounds of Formula II where R³=Z³-OH),II-H (compounds of Formula II where R³=Z-A⁵(R³¹³)(R³²³)_(aa)), I-F(compounds of Formula I-AA where R³=Z-OH), and I-G (compounds of FormulaI-AA where R³=Z-A⁵(R³¹³)(R³²³)_(aa)) were prepared as shown below inScheme 22:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I; aa ═0 or 1; and A⁵=N, O or S.

In a typical preparation of compound of Formula I-F and 1-G, thefollowing transformations occurred: Compound of Formula II-F was reducedwith a suitable reducing agent in a suitable solvent, such as sodiumborohydride in methanol to afford compound of Formula II-G. Compound ofFormula II-G was subjected to previously described ammonolysisconditions to afford compound of Formula I-F. Additionally, compounds ofFormula II-F can be reacted with various amines under reductiveamination conditions (NaBH₃CN or NaBH(OAc)₃ with HA⁵(R³¹³)(R³²³)_(aa)where d=0, A⁵=N, and R³¹³ and R³²³ are as previously described forcompound of Formula I) to afford compounds of Formula II-H where d=0,A⁵=N, and R³¹³ and R³²³ are as previously described for compound ofFormula I. Subsequent reaction of compounds of Formula II-H (compoundsof Formula II where R³=Z-A⁵(R³¹³)(R³²³)_(aa) where d=0, A⁵=N, and R³¹³and R³²³ are as previously described for compound of Formula I) withpreviously described ammonolysis conditions afforded compounds ofFormula I-G. Furthermore, compounds of Formula II-H from II-G and I-Gfrom I-F can be synthesized according to the conditions described inScheme 19 for the transformations of II-B to II-D and I-B to I-C,respectively.

The compounds of Formula I-C′″ (compounds of Formula I-AA whereR³=Z-CH₂—N(R³¹³)(R³²³)) were prepared as shown below in Scheme 23:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I and A⁴=suitable leaving group such as Cl, OTs, OMs or OTf.

In a typical preparation of compound of Formula I-C′″ (compounds ofFormula I-AA where R³=Z-CH₂—N(R³¹³)(R³²³), the following transformationsoccurred: Compounds of Formula II-J (compounds of Formula II whereR³=Z=CH₂) were reacted with a suitable hydroborating agent such asdiborane, 9-borabicyclo[3.3.1]nonane (9-BBN), catecholborane and thelike, in a suitable solvent such as THF followed by treatment with ansuitable oxidizing agent such as hydrogen peroxide in basic aqueoussolution or NaBO₃.H₂O to afford compounds of Formula II-B. Furtherreaction of compounds of Formula II-B with previously describedammonolysis conditions afforded compounds of Formula I-B. The hydroxygroup of compounds of Formula I-B was then converted to a suitableleaving group, A⁴, such OTs, OMs, or OTf, by reaction with Ts₂O, Ms₂O,or Tf₂O, respectively, to afford compounds of Formula I-H. Furtherreaction of compounds of Formula I-H with HN(R³¹³)(R³²³) where R³¹³ andR³²³ are as previously described for compounds of Formula I affordedcompound of Formula I-C′″ (compounds of Formula I-AA whereR³=Z-CH₂—N(R³¹³)(R³²³)).

The compounds of Formula I-C′″ (compounds of Formula I-AA where R³Z-OH(CH₂OH)), I-K (compounds of Formula I-AA where R³=Z=O), and I-L(compounds of Formula I-AA where R³-Z-NR³¹³R³²³) were prepared as shownbelow in Scheme 24:

where Q¹, R³¹² and R³²² are as defined previously for compound ofFormula I.

In a typical preparation of compound of Formula I-J (compounds ofFormula I-AA where R³=Z-OH(CH₂OH)), 1-K (compounds of Formula I-AA whereR³=Z=O), and I-L (compounds of Formula I-AA where R³=Z-NR³¹²R³²²)compound of Formula II-J was treated under (compounds of Formula IIwhere R³=Z=CH₂) was reacted with a suitable dihydroxylating agent suchas osmium tetraoxide in the presence of NMO in a suitable solvent suchas THF to afford compound of Formula I-K (compounds of Formula II whereR³=Z-OH(CH₂OH)) as a mixture of cis and trans isomers. Compounds ofFormula II-K (compounds of Formula II where R³=Z-OH(CH₂OH)) were treatedwith a suitable oxidizing agent, such as but not limited to, NaIO₄,converting the diol into a ketone moiety, affording compound of FormulaII-L (compounds of Formula II where R³=Z=O). Compound of Formula II-L(compounds of Formula II where R³=Z=O) was then treated under typicalreductive amination conditions, involving a suitable amine, HNR³¹²R³²²and a suitable reducing agent, such as but not limited to, NaBH(OAc)₃ orNaBH(CN)₃, affording compound of Formula II-M (compounds of Formula IIwhere R³=Z-NR³¹²R³²²). Compound of Formula II-M (compounds of Formula IIwhere R³=Z-NR³¹²R³²²) was treated under ammonolysis conditions, ammoniain isopropanol in a stainless steel bomb at 110° C., to afford compoundof Formula I-L (compounds of Formula I-AA where R³=Z-NR³¹²R³²²).Moreover, compound of Formula II-K (compounds of Formula II whereR=Z-OH(CH₂OH)) was treated under the ammonolysis conditions describedabove to afford compound of Formula I-J (compounds of Formula I-AA whereR³=Z-OH(CH₂OH)) as a mixture of isomers. Compound of Formula I-J(compounds of Formula I-AA where R³=Z-OH(CH₂OH) was treated with asuitable oxidizing agent, such as but not limited to, NaIO₄, convertingthe diol into a ketone moiety, affording compound of Formula I-K(compounds of Formula I-AA where R³=Z=O), which was treated under thetypical reductive amination conditions described above to affordcompound of Formula I-L (compounds of Formula I-AA where R³═NR³¹²R³²²).

The compounds of Formula I-N (compounds of Formula I-AA whereR³=Z-OH(CH₂NR³¹³R³²³)) were prepared as shown below in Scheme 25:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I; A⁴=suitable leaving group such as OTs, OMs, or OTf.

In a typical preparation of compounds of Formula I-N (compounds ofFormula I-AA where R³=Z-OH(CH₂NR³¹³R³²³)), the primary hydroxyl group ofcompound of Formula I-J (compounds of Formula I-AA where R³=Z-OH(CH₂OH)was converted to a suitable leaving group, A⁴, such as OTs, OMs, or OTf,by reaction with Ts₂O, Ms₂O, or Tf₂O in the presence of a suitable basesuch as diisopropylamine or pyridine and solvent such as THF ormethylene chloride to afford compound of Formula I-M (compounds ofFormula I-A where R³=Z-OH(CH₂A⁴)). Reaction of compound of Formula I-M(compounds of Formula I-AA where R³=Z-OH(CH₂A⁴)) with HN(R³¹³)(R³²³) ina suitable solvent such as THF or methylene chloride afforded compoundof Formula I-N (compounds of Formula I where R³=Z-OH(C₂NR³¹³R³²³)).

The compounds of Formula I-O (compounds of Formula I whereR³=Z³-OH(G¹¹)) were prepared as shown below in Scheme 26:

where Q¹ and G¹¹ are as defined previously for compound of Formula I.

In a typical preparation of compounds of Formula I-0 (compounds ofFormula I where R³=Z-OH(G¹¹)), the ketone moiety of compound of FormulaII-L (compounds of Formula II where R³=Z=O) was reacted with a suitablenucleophilic reagent such as MeMgBr or MeLi in a suitable solvent suchas THF to afford compound of Formula II-N (compounds of Formula II whereR³=Z-OH(G¹¹)). Compound of Formula II-N (compounds of Formula II whereR³=Z-OH(G¹¹)) was reacted under ammonolysis conditions, ammonia inisopropanol in a stainless steel bomb at 110° C., to afford compound ofFormula I-0 (compounds of Formula I where R³=Z-OH(G¹¹)). Additionally,compound of Formula I-0 (compounds of Formula I where R³=Z-OH(G¹¹)) wasprepared by reacting compound of Formula I-K (compounds of Formula I-AAwhere R³=Z=O) with a suitable nucleophilic reagent such as MeMgBr orMeLi in a suitable solvent such as THF.

The conversion of compounds of Formula I-PP′ and I-P′ to compounds ofFormula I-RR an I-R, respectively may be accomplished by reaction with aboronic acid ester using so-called “Liebeskind-Srogl” conditions such asthose described in Organic Letters, (2002), 4(6), 979 or Synlett,(2002), (3), 447.

A compound of Formula I-A Bis equal to compound of Formula I whereinX₁═CH, X₂, X₄ and X₅═N, and X₃, X₆ and X₇═C; Q¹ is as defined for acompound of Formula I; R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl,aminomethylcycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl,spiroalkyl, or heterospiroalkyl, any of which is optionally substitutedby one or more independent G¹¹ substituents; and G¹¹ is as defined for acompound of Formula I:

Method AB was used when preparing compounds of Formula I-AB as shownbelow in Scheme 28:

Method AB:

where Q¹ and R³ are as defined previously for compound of Formula I-AB,A¹¹=halogen such as Cl, Br, or I, and Q¹-B(OR)₂=suitable boronicacid/ester.

In a typical preparation of compounds of Formula I-AB, compound ofFormula I-ABA was reacted with a suitable boronic acid/ester of FormulaXIV-Z (Q¹-B(OR)₂) in a suitable solvent via typical Suzuki couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent systems wereTHF/water and DMF/water. The above process was carried out attemperatures between about 20° C. and about 120° C. Preferably, thereaction was carried out between 80° C. and about 100° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of Formula I-AB from I-ABA. Forexample, compound of Formula I-ABA could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula I-ABA wherein R³ is C₁₋₁₀alkyl,cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents, of Scheme 28 were prepared as shown below in Scheme 29:

where R³ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; G¹¹ is as defined previously for compoundof Formula I, and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula I-ABA, a compound ofFormula I-ABB was reacted with an alcohol R³—OH under typical Mitsunobuconditions in a suitable solvent in the presence of suitable reactants.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylfomamide DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH₃CN);chlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was THF. Suitable reactants for use in the aboveprocess included, but were not limited to, triphenylphosphine and thelike, and an azodicarboxylate (DIAD, DEAD, DBAD). The preferredreactants were triphenylphosphine or resin-bound triphenylphosphine andDIAD. The above process may be carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction was carried outbetween about 0° C. and 25° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Generally, oneequivalent of triphenylphosphine, DL), and RASH was used per equivalentof compound of Formula I-ABB.

Alternatively, the compounds of Formula I-ABA may be prepared byalkylating compounds of Formula I-ABB with an alkylating agent R³-LG,wherein LG is a leaving group including, but not limited to, chloride,bromide, iodide, tosylate, mesylate, trifluoromethanesulfonate, undertypical alkylation conditions known to someone skilled in the art.

Preferably, in compounds of Formula I-ABB, A¹¹=Br and I. These compoundsare known (A¹¹=I: H. B. Cottam et al., J. Med. Chem. 1993, 36(22),3424-3430; A¹¹=Br: T. S. Leonova et al., Khim. Geterotsikl. Soedin.1982, (7), 982-984).

Compound of Formula I-AC is equal to compound of Formula I wherein X₁and X₅═CH, X₂ and X₄═N, and X₃, X₆ and X₇═C; Q¹ is as defined for acompound of Formula I; R³ is C₀₋₁₀alkyl, cycloC₃₋₁₀alkyl,bicycloC₅₋₁₀alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, or heterospiroalkyl,any of which is optionally substituted by one or more independent G¹¹substituents; and G¹¹ is as defined for a compound of Formula I:

Method AC was used when preparing compounds of Formula I-AB as shownbelow in Scheme 30:

Method AC:

where Q¹ and R³ are as defined previously for compound of Formula I-AC,A¹¹=halogen such as Cl, Br, or I and Q¹-B(OR)₂=suitable boronicacid/ester.

In a typical preparation of compounds of Formula I-AC, compound ofFormula I-ACA was reacted with a suitable boronic acid/ester XIV-Z(Q¹-B(OR)₂) in a suitable solvent via typical Suzuki couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired mixturesof these solvents were used, however, the preferred solvent systems wereTHF/water and DMF/water. The above process was carried out attemperatures between about 20° C. and about 120° C. Preferably, thereaction was carried out between 80° C. and about 10° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of formula I-AC from I-ACA. Forexample, compound of Formula I-ACA could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula I-ACA of Scheme 30 were prepared as shown belowin Scheme 31:

where R³ is as defined previously for compound of Formula I-AC, andA¹¹=halogen such as CL Br, or I.

In a typical preparation of compounds of Formula I-ACA, compound ofFormula XV was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 80° C. and about 100°C. The above process to produce compounds of the present invention waspreferably carried out in a glass pressure tube or a stainless steelreactor. Preferably, an excess of ammonia was used.

The compounds of Formula XVA (=compounds of Formula XV of Scheme 31wherein R³ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroakyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents) were prepared as shown below in Scheme 32:

where R³ is C₁₋₁₀alkyl, cycloC₃₋₁₀alkyl, bicycloC₅₋₁₀alkyl, aralkyl,heteroaralkyl, heterocyclyl, heterobicycloC₅₋₁₀alkyl, spiroalkyl, orheterospiroalkyl, any of which is optionally substituted by one or moreindependent G¹¹ substituents; G¹¹ is as defined previously for compoundof Formula I; and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula XVA, a compound ofFormula XVI was reacted with an alcohol R³OH under typical Mitsunobuconditions in a suitable solvent in the presence of suitable reactants.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); chlorinated solvents such as methylene chloride (CH₂Cl₂) orchloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was THF. Suitable reactants for use inthe above process included, but were not limited to, triphenylphosphineand the like, and an azodicarboxylate (DIAD, DEAD, DBAD). The preferredreactants were triphenylphosphine or resin-bound triphenylphosphine andDIAD. The above process may be carried out at temperatures between about−78° C. and about 100° C. Preferably, the reaction was carried outbetween about 0° C. and 25° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired. Generally, oneequivalent of triphenylphosphine, DIAD, and R³—OH was used perequivalent of compound of Formula XVI.

Alternatively, the compounds of Formula XVA may be prepared byalkylating compounds of Formula XVI with an alkylating agent R³-LG,wherein LG is a leaving group including, but not limited to, chloride,bromide, iodide, tosylate, mesylate, trifluoromethanesulfonate, undertypical alkylation conditions known to someone skilled in the art.

The compounds of Formula XVB (compounds of Formula XV of Scheme 31wherein R³ is aryl or heteroaryl, optionally substituted by one or moreindependent G¹¹ substituents) were prepared as shown below in Scheme 33:

where R³ is aryl or heteroaryl, optionally substituted by one or moreindependent G¹¹ substituents, G¹¹ is as defined previously for compoundof Formula I; and A¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula XVB, compound ofFormula XVI was reacted with a suitable boronic acid of FormulaR³—B(OH)₂ in a suitable solvent via typical copper(II)-mediated couplingprocedures. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme,1,4-dioxane, and the like; dimethylformamide (DMF);N-methylpyrrolidinone (NMP); chlorinated solvents such as methylenechloride (CH₂Cl₂). If desired, mixtures of these solvents were used,however, the preferred solvent was methylene chloride (CH₂Cl₂). Suitablereactants for use in the above process included, but were not limitedto, copper(II) acetate (Cu(OAc)₂, copper(II) triflate (Cu(OTf)₂), andthe like, and a base pyridine, and the like). The preferred reactantswere Cu(OAc)₂ and pyridine. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure under air, although higher or lower pressures could be used ifdesired. Preferably, the reaction was cried out at about 22C. Generally,1.5 eq, of copper(II) acetate, 2 eq. of pyridine, and 2 eq. of boronicacid of Formula R³—B(OH) were used per equivalent of compound of FormulaXVI.

All compounds of Formula XVI are known in the literature (A¹¹=I: L. B.Townsend et al., J. Med. Chem. 1990, 33, 1984-92; A¹¹=Br, Cl: L. B.Townsend et al., J. Med. Chem., 1988, 31, 2086-2092). Preferably, A¹¹=Brand I.

Both R³ and Q¹ in the compounds described herein in some instancescontain functional groups that can be further manipulated. It would beappreciated by those skilled in the art that such manipulation offunctional groups could be accomplished with key intermediates or withlate stage compounds. Such functional group transformations areexemplified in the following Schemes 3435 as well as in the experimentalsection but are in no way meant to limit the scope of suchtransformations.

The compounds of Formula I-ACA′ (=compounds of Formula I-ACA whereR³=Z-CONR³¹²R³²²) were prepared from compounds of Formula XV′(=compounds of Formula XV where R³=Z-CO₂A³) as shown below in Scheme 34:

where R³¹² and R³²² are as defined previously for compound of Formula I;A¹¹=halogen such as Cl, Br, or I; and A³=hydrogen or alkyl such asmethyl or ethyl.

In a typical preparation of compound of Formula I-ACA′, when A³=alkyland R³¹² and R³²² were both equal to H, reaction of compound of FormulaXV′ with ammonia in a suitable solvent, afforded compound of FormulaI-ACA′. Suitable solvents for use in the above process included, butwere not limited to, ethers such as tetrahydrofuran (THF), glyme, andthe like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO);acetonitrile; alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; and chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixturesof these solvents were used, however, the preferred solvent wasisopropanol. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 80° C. and about 100° C. The above process to produce compoundsof the present invention was preferably carried out in a glass pressuretube or a stainless steel reactor. Preferably, an excess of ammonia wasused. Additionally, in a typical preparation of compound of FormulaI-ACA′ (compounds of Formula I-ACA where R³=Z-CONR³¹²R³²²), compound ofFormula XV′ (compounds of Formula XV′ where R³=Z-CO₂A³) was reacted withHNR³¹²R³²² followed by ammonia in a suitable solvent. When A³=H, typicalcoupling procedures (such as conversion of —O₂H to —COCl via treatmentwith SOCl₂ or oxalyl chloride followed by reaction with HNR³¹²R³²² ortreatment of —CO₂H and HNR³¹²R³²² with EDC or DCC in conjunction withDMAP, HOBT, or HOAt and the like) were employed to afford thetransformation of a carboxylic acid to an amide. When A³ alkyl such asmethyl or ethyl, treatment of the ester with Al(NR³¹²R³²²) affordedconversion of —CO₂A³ to —CO(NR³¹²R³²²). Subsequent treatment withammonia afforded compounds of Formula I-ACA′.

The chemistry shown in Scheme 34 can also be applied to compounds withQ¹ in place of A¹¹.

The compounds of Formula XVIII (compounds of Formula XV, I-ACA, or I-ACwhere R³=Z-CH₂OH), XIX (compounds of Formula XV, I-ACA, or I-AC whereR³═CH₂LG), and XX (compounds of Formula XV, I-ACA, or I-AC whereR³=Z-CH₂A⁵(R³¹³)R³²³)_(aa)) were prepared as shown below in Scheme 35:

where Q¹, R³¹³, and R³²³ are as defined previously for compound ofFormula I; LG=suitable leaving group such as tosylate, mesylate,trifluoromethanesulfonate, or halo such as chloro, bromo, or iodo; aa ═0or 1; A³=hydrogen or alkyl such as methyl or ethyl; A¹¹=halogen such asCl, Br, or I; A¹²=C or NH₂; A¹³=A¹¹ or Q¹; and A⁵=N, O or S.

The following table indicates the relations between the compounds ofFormulas XVII-XX, A¹², A¹³, compounds of Formulas I-AC, I-AC, and XV,and R³.

Compound of wherein and . . . is equal to Formula . . . A¹² = A¹³ =Formula . . . wherein R³ = XVII Cl A¹¹ XV Z—CO₂A³ XVII NH₂ A¹¹ I-ACAZ—CO₂A³ XVII NH₂ Q¹ I-AC Z—CO₂A³ XVIII Cl A¹¹ XV Z—CH₂OH XVIII NH₂ A¹¹I-ACA Z—CH₂OH XVIII NH₂ Q¹ I-AC Z—CH₂OH XIX Cl A¹¹ XV Z—CH₂LG XIX NH₂A¹¹ I-ACA Z—CH₂LG XIX NH₂ Q¹ I-AC Z—CH₂LG XX Cl A¹¹ XV Z—CH₂A⁵R²(R⁴)_(d)XX NH₂ A¹¹ I-ACA Z—CH₂A⁵R²(R⁴)_(d) XX NH₂ Q¹ I-AC Z—CH₂A⁵R²(R⁴)_(d)

In a typical preparation of compound of Formula XVII (compounds ofFormula XV, I-ACA, or I-AC, where R³=Z-CH₂OH), compound of Formula XVII(compounds of Formula XV, I-ACA, or I-AC, where R³=Z-CO₂A³) is treatedwith a suitable reducing agent, such as lithium aluminum hydride ordiisobutylaluminum hydride, in a suitable solvent, such as THF ormethylene chloride, to afford compound of Formula XVIII. In a typicalpreparation of compound of Formula XX (compounds of Formula XV, I-ACA,or I-AC, where R³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)), the hydroxy group ofcompound of Formula XVIII was converted to a suitable leaving group, LG,such as Cl or tosylate, mesylate, or triflate, by reaction with SOCl₂ orTs₂O, Ms₂O, or Tf₂O to afford compound of Formula XIX (compounds ofFormula XV, I-ACA, or I-AC, where R³=Z-CH₂LG). Reaction of compound ofFormula XIX with HA⁵(R³¹³)(R³²³)_(aa) afforded compound of Formula XX.Furthermore, compound of Formula XVIII can be directly converted tocompound of Formula XX by treating compound of Formula XVIII withvarious alkylating agents or under typical Mitsunobu reaction conditionsto afford compounds of Formula XX (compounds of Formula XV, I-ACA, orI-AC, where R³=Z-CH₂A⁵(R³¹³)(R³²³)_(aa)) in which A⁵=O, aa=0, andR³¹³=alkyl or aryl). Someone skilled in the an will choose the mostappropriate stage during the sequence shown in Scheme 35 to convertA¹²=Cl to A¹²═NH₂ as described in Scheme 31, and to convert A¹³=A¹¹ toA¹³=Q¹ as described in Scheme 30, if applicable.

An alternative preparation of compounds of Formula I-AC is shown inScheme 36.

where Q¹ and R³ are as defined previously for compound of Formula I; andA¹¹=halogen such as Cl, Br, or I.

The compounds of Formula XXI may be prepared from aldehydes Q¹-CHO (seeScheme 14 for their preparation) by addition of methyllithium or amethyl Grignard reagent, followed by oxidation of the resulting alcoholto the ketone of Formula XXI. Other compounds are commercially availableor can be prepared by methods well known to someone skilled in the art,see: Larock, R. C. Comprehensive Organic Transformations, 2^(nd) ed.;Wiley and Sons: New York, 1999, 1197 ff. Reaction of compounds ofFormula XXI under typical halogenation conditions with typicalhalogenating agents including, but not limited to, Br₂, NBS, pyridiniumperbromide, or CuBr₂ (for A¹¹=Br), or NCS or SO₂Cl₂ (for A¹¹=Cl) givesthe compounds of Formula XXII. Their reaction with amines of FormulaH₂N—R³ gives the aminoketones of Formula XXIII that are converted toaminocyanopyrroles of Formula XXIV by reaction with malononitrile underbasic conditions. Finally, reaction of compounds of Formula XXIV undertypical cyclization conditions gives the compounds of Formula I-AC.Conditions for this cyclization include, but are not limited to, heatingwith formamide; heating with formamide and ammonia; sequential treatmentwith a trialkyl orthoformate, ammonia, and a base; sequential treatmentwith formamidine and ammonia.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

Compound of Formula I-AQ is equal to compound of Formula I whereinX₁═CH; X₂, X₃ and X₅═N; X₄, X₆, and X₇═C and J=H or NH₂

Method AQ was used when preparing compounds of Formula I-AQ as shownbelow in Scheme 37:

Method AQ:

where Q¹ and R³ are as defined previously for compound of Formula I,A¹¹=halogen such as Cl, Br, or I; B(OR)₂=suitable boronic acid/ester andJ=H or NH₂.

In a typical preparation of compounds of Formula I-AQ, compound ofFormula II-Q was reacted with a suitable boronic acid/ester (Q¹-B(OR)₂)in a suitable solvent via typical Suzuki coupling procedures. Suitablesolvents for use in the above process included, but were not limited to,water, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was glyme/water. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 80° C. and about 100°C. The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

One skilled in the art will appreciate that alternative methods may beapplicable for preparing compounds of Formula I-AQ from II-Q. Forexample, compound of Formula II-Q could be reacted with a suitableorganotin reagent Q¹-SnBu₃ or the like in a suitable solvent via typicalStille coupling procedures.

The compounds of Formula II-Q of Scheme 37 were prepared as shown belowin Scheme 38.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I; and J=H or NH₂.

In a typical preparation of compounds of Formula II-Q, compound ofFormula II-Q was reacted with phosphorus oxychloride (POCl₃) andtriazole, and pyridine followed by ammonia (NH₃) in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;alcohols such as methanol, ethanol, isopropanol, trifluoroethanol, andthe like; and chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃). If desired, mixtures of these solvents were used,however, the preferred solvent was isopropanol. The above process wascarried out at temperatures between about −20° C. and about 50° C.Preferably, the reaction was carried out between 0° C. and about 25° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III-Q of Scheme 38 were prepared as shown belowin Scheme 39.

where R³ is as defined previously for compound of Formula I; A¹¹=halogensuch as Cl, Br, or I; and J=H or NH₂.

In a typical preparation of a compound of Formula III-Q, intermediateV-Q was converted to compound of Formula IV-Q. Intermediate of FormulaV-Q was treated with phosphorus oxychloride (POCl₃) in a suitablesolvent at a suitable reaction temperature. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like, chlorinated solvents such asmethylene chloride (CH₂Cl₂) or chloroform (CHCl₃), and acetonitrile. Ifdesired, mixtures of these solvents were used. The preferred solvent wasacetonitrile. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 40° C. and about 95° C. The above process to produce compoundsof the present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Intermediate for Formula III-Q was prepared by reacting intermediate ofFormula IV-Q with a suitable halogenating agent. Suitable halogenatingagents included, but were not limited to, Br₂, I₂, Cl₂,N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. Thepreferred halogenating agent was N-iodosuccinimide. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), glyme, and the like; dimethylformamide(DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcohols such asmethanol, ethanol, isopropanol, trifluoroethanol, and the like; andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was DMF. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 75° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

Compounds of Formulae IV-Q and III-Q where J=NH₂ can be respectivelyconverted into the compounds of Formulae IV-Q and III-Q where J=H, bydiazotisation procedures known to those skilled in the art. A typicalprocedure includes the treatment of a compound of Formula IV-Q or III-Qwhere J=NH₂ with tert-butylnitrite in a suitable solvent such a THF orDMF.

The compounds of Formula V-Q of Scheme 39 were prepared as shown belowin Scheme 40:

where R¹ is as defined previously for compound of Formula I; A¹=OH,alkoxy, or a leaving group such as chloro or imidazole; and J=H or NH₂.

In a typical preparation, of a compound of Formula V-Q, a compound ofFormula VI-Q and compound of Formula V were reacted under suitableamide-coupling conditions. Suitable conditions include but are notlimited to treating compounds of Formula VI-Q and V (when A¹=OH) withcoupling reagents such as DCC or EDC in conjunction with DMAP, HOBt,HOAt and the like, or reagents like EEDQ. Suitable solvents for use inthe above process included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such aschloroform or methylene chloride. If desired, mixtures of these solventswere used, however the preferred solvent was methylene chloride. Theabove process was carried out at temperatures between about 0° C. andabout 80° C. Preferably, the reaction was carried out at about 22° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Alternatively, compounds of Formula VI-Q and V (whereA¹=F, Cl, Br, I) were reacted with bases such as triethylamine orethyldiisopropylamine and the like in conjunction with DIP and the like.Suitable solvents for use in this process included, but were not limitedto, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (0M); dimethyl sulfoxide DMSO); acetonitrile;pyridine; halogenated solvents such as chloroform or methylene chloride.If desired, mixtures of these solvents were used, however the preferredsolvent was DMF. The above process was carried out at temperaturesbetween about −20° C. and about 40° C. Preferably, the reaction wascarried out between 0° C. and 25° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of compounds of Formula VI-Qand V (where A¹=F, Cl, Br, I) and base and substoichiometric amounts ofDMAP were preferably used although higher or lower amounts were used ifdesired. Additionally, other suitable reaction conditions for theconversion of an amine (compound of Formula VI-Q) to an amide (compoundof Formula V-Q) can be found in Larock, R. C. Comprehensive OrganicTransformations, 2^(nd) ed.; Wiley and Sons: New York, 1999, pp1941-1949.

The compounds of Formula VI-Q of Scheme 40 where J=H were prepared asshown below in Scheme 41:

In a typical preparation, of a compound of Formula VI-Q, a compound ofFormula VII-Q is reacted under suitable reaction conditions in asuitable solvent. Suitable conditions include treatment of compound ofFormula VII-Q with hydrazine or methyl hydrazine in a suitable solvent.Suitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile;halogenated solvents such as chloroform or methylene chloride; alcoholicsolvents such as methanol and ethanol. If desired, mixtures of thesesolvents may be used, however the preferred solvents were ethanol andmethylene chloride. The above process was carried out at temperaturesbetween about 0° C. and about 80° C. Preferably, the reaction wascarried out at about 22° C. The above process to produce compounds ofthe present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.Substantially equimolar amounts of reactants were preferably usedalthough higher or lower amounts were used if desired.

Compounds of Formula VI-Q where J=NH₂ may be prepared according to theprocedures described in J. Het. Chem., (1984), 21, 697.

The compounds of Formula VII-Q of Scheme 41 were prepared as shown belowin Scheme 42:

In a typical preparation of a compound of Formula VII-Q, a compound ofFormula VIII-Q was reacted with Raney Nickel in a suitable solventSuitable solvents for use in the above process included, but were notlimited to, ethers such as tetrahydrofuran (THF), glyme, and the like;dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 100° C. Preferably, the reaction was carried out at about 80° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired. Additionally a compound of Formula VII-Q can beprepared by reacting a compound of Formula VIII-Q with a suitableoxidizing agent in a suitable solvent. A suitable oxidizing agentincludes, but is not limited to hydrogen peroxide (H₂O₂), 3-chloroperoxybenzoic acid (mCPBA) and the like. Suitable solvents for use inthe above process included, but were not limited to, ethers such as THF,glyme, and the like; DMF; DMSO; CH₃CN; and dimethylacetamide (DMA);chlorinated solvents such as CH₂Cl₂ or CHCl₃ If desired, mixtures ofthese solvents were used, however, the preferred solvent was DMA. Theabove process may be carried out at temperatures between about 0° C. and100° C. Preferably, the reaction was carried out at about rt to 70° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula VIII-Q of Scheme 42 were prepared as shownbelow in Scheme 43:

In a typical preparation of a compound of Formula VIII-Q, a compound ofFormula IX-Q was reacted with thiosemicarbazide and a suitable base in asuitable solvent. Suitable bases include, but were not limited totriethylamine, ethyldiisopropylamine and the like. Suitable solvents foruse in the above process included, but were not limited to, ethers suchas tetrahydrofuran (THF), glyme, and the like, dimethylformamide (DMF);dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); acetonitrile(CH₃CN); alcohols such as methanol, ethanol, isopropanol,trifluoroethanol, and the like; chlorinated solvents such as methylenechloride (CH₂Cl₂) or chloroform (CHCl₃). If desired, mixtures of thesesolvents were used, however, the preferred solvent was ethanol. Theabove process may be carried out at temperatures between about rt andabout 10° C. Preferably, the reaction was carried out between about 40°C. and 80° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Substantiallyequimolar amounts of reactants were preferably used although higher orlower amounts were used if desired. Compound of Formula IX-Q can beprepared according to literature procedures Knutsen, Lars J. S. et. al.,J. Chem. Soc. Perkin Trans 1: Organic and Bio-Organic Chemistry(1972-1999), 1984, 229-238.

It would be appreciated by those skilled in the art that in somesituations, a substituent that is identical or has the same reactivityto a functional group which has been modified in one of the aboveprocesses, will have to undergo protection followed by deprotection toafford the desired product and avoid undesired side reactions.Alternatively, another of the processes described within this inventionmay be employed in order to avoid competing functional groups. Examplesof suitable protecting groups and methods for their addition and removalmay be found in the following reference: “Protective Groups in OrganicSyntheses”, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, 1989.

Method A W was also used when preparing compounds of Formula II-Q asshown below in Scheme 44:

Method AW:

where Q¹ and R³ are as defined previously for compound of Formula I, andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of compounds of Formula II-Q, compound ofFormula III-W was reacted with ammonia in a suitable solvent. Suitablesolvents for use in the above process included, but were not limited to,ethers such as tetrahydrofuran (THF), glyme, and the like; alcohols suchas methanol, ethanol, isopropanol, trifluoroethanol, and the like; andchlorinated solvents such as methylene chloride (CH₂Cl₂) or chloroform(CHCl₃). If desired, mixtures of these solvents were used, however, thepreferred solvent was isopropanol. The above process was cared out attemperatures between about 0° C. and about 50° C. Preferably, thereaction was carried out at between 0° C. and about 22° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired. Substantially equimolar amounts ofreactants were preferably used although higher or lower amounts wereused if desired.

The compounds of Formula III-W of Scheme 44 were prepared as shown belowin Scheme 45.

where R³ is as defined previously for compound of Formula I andA¹¹=halogen such as Cl, Br, or I.

In a typical preparation of a compound of Formula III-W, compound V-Wwas converted to compound of Formula IV-W. Compound of Formula V-W wastreated with phosphorus oxychloride (POCl₃) or the isolated “Vilsmeirsalt” [CAS# 33842-02-3] in a suitable solvent at a suitable reactiontemperature. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like, chlorinated solvents such as methylene chloride (CH₂Cl₂)or chloroform (CHCl₃), and acetonitrile (CH₃CN). If desired, mixtures ofthese solvents were used. The preferred solvent was acetonitrile. Theabove process was cared out at temperatures between about −78° C. andabout 120° C. Preferably, the reaction was carried out between 40° C.and about 95° C. The above process to produce compounds of the presentinvention was preferably carried out at about atmospheric pressurealthough higher or lower pressures were used if desired. Compounds ofFormula III-W were prepared by reacting compound of Formula IV-W with asuitable halogenating agent Suitable halogenating agents included, butwere not limited to, Br₂, I₂, Cl₂, N-chlorosuccinimide,N-bromosuccinimide, or N-iodosuccinimide. The preferred halogenatingagent was N-iodosuccinimide, Suitable solvents for use in the aboveprocess included, but were not limited to, ethers such astetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF);dimethyl sulfoxide (DMSO); acetonitrile; alcohols such as methanol,ethanol, isopropanol, trifluoroethanol, and the like; and chlorinatedsolvents such as methylene chloride (CH₂Cl₂) or chloroform (CHCl₃). Ifdesired, mixtures of these solvents were used, however, the preferredsolvent was DMF. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 40° C. and about 75° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Substantially equimolar amounts of reactants were preferablyused although higher or lower amounts were used if desired.

The compounds of Formula VI-W of Scheme 45 were prepared as shown belowin Scheme 46.

where R³ is as defined previously for compound of Formula I, X¹²=azido,or mono- or di-protected amino and A¹=OH, alkoxy or a leaving group suchas chloro or imidazole.

In a typical preparation of a compound of Formula V-W, compound VI-W wasreacted with compound V under suitable amide coupling conditions.Suitable conditions include but are not limited to those described forthe conversion of compound XIII to compound XII as shown in Scheme 10.Compounds of Formula VI-W were prepared from compounds of Formula VII-W.A typical procedure for the conversion of compounds of Formula VII-W tocompounds of Formula VI-W involves subjecting a compound of FormulaVII-W, where X¹²=azido, to reducing conditions such as, but not limitedto, catalytic hydrogenation in a suitable solvent at a suitable reactiontemperature. Suitable solvents for use in the above process included,but were not limited to, ethers such as tetrahydrofuran (THF), glyme,and the like, alcoholic solvents such as methanol, ethanol and the like,esters such as ethyl acetate, methyl acetate and the like. If desired,mixtures of these solvents were used. The preferred solvents were ethylacetate and methanol. The above process was carried out at temperaturesbetween about −78° C. and about 120° C. Preferably, the reaction wascarried out between 40° C. and about 95° C. The above process to producecompounds of the present invention was preferably carried out at aboutatmospheric pressure although higher or lower pressures were used ifdesired. Alternatively, when X¹²=azido, the reduction to compounds ofFormula VI-W could be achieved by treatment of a compound of FormulaVII-W with triaryl- or trialkylphosphines in the presence of water in asuitable solvent at a suitable reaction temperature. Suitable solventsfor use in the above process included, but were not limited to, etherssuch as tetrahydrofuran (THF), dioxane and the like, alcoholic solventssuch as methanol, ethanol and the like, esters such as ethyl acetate,methyl acetate and the like, DMF, acetonitrile, and pyridine. Ifdesired, mixtures of these solvents were used. The preferred solventswere THF and acetonitrile. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired.

Where X¹²=mono- or di-protected amino, the deprotection could beeffected by the procedures known to those skilled in the art and asdisclosed in: “Protective Groups in Organic Syntheses”, T. W. Greene andP. G. M. Wuts, John Wiley and Sons, 1989.

The compounds of Formula VII-W of Scheme 46 were prepared as shown belowin Scheme 47:

where R₃ is as defined previously for compound of Formula I, X¹² is asdefined for a compound of Formula VII-W and A¹²=iodo, bromo, chloro,tosylate, mesylate or other leaving group.

In a typical preparation of a compound of Formula VII-W where X¹²=azide,compound VIII-W was reacted with an azide salt, such as lithium orsodium azide in suitable solvent at a suitable reaction temperature.Suitable solvents for use in the above process included, but were notlimited to, alcoholic solvents such as ethanol, butanol and the like,esters such as ethyl acetate, methyl acetate and the like, DMF,acetonitrile, acetone DMSO. If desired, mixtures of these solvents wereused. The preferred solvents were acetone and DMF. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 40° C. and about 95° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired. Alternatively, where X¹²=mono- ordi-protected amino, compounds of Formula VIII-W were reacted withsuitably protected amines where the protecting group is chosen such thatthe nucleophilic nature of the nitrogen is either retained or where itcan be enhanced by the action of a reagent such as a base. Those skilledin the art will recognize that such protecting groups include, but arenot limited to, benzyl, trityl, allyl, and alkyloxycarbonyl derivativessuch as BOC, CBZ and FMOC.

Compounds of Formula VIII-W where A¹²=halogen, are prepared fromcompounds of Formula XI-W. In a typical procedure, compounds of FormulaXI-W are treated with halogenating reagents such as but not limited toN-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide,trichloroisocyanuric acid, N,N′-1,3-dibromo-5,5-dimethylhydantoin,bromine and iodine, preferably in the presence of one or more radicalsources such as dibenzoyl peroxide, azobisisobutyronitrile or light insuitable solvent at a suitable reaction temperature. Suitable solventsfor use in the above process included, but were not limited to,chlorinated solvents such as carbon tetrachloride, dichloromethane,α,α,α-trifluorotoluene and the like, esters such as methyl formate,methyl acetate and the like, DMF, acetonitrile. If desired, mixtures ofthese solvents were used. The preferred solvents were carbontetrachloride and α,α,α-trifluorotoluene. The above process was carriedout at temperatures between about −78° C. and about 120° C. Preferably,the reaction was carried out between 40° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired.

Alternatively, compounds of Formula VIII-W where A¹²=tosylate ormesylate were prepared from compounds of Formula X-W as shown in Scheme48. In a typical preparation of a compound of Formula VIII-W, a compoundof Formula X-W was reacted with a sulfonylating reagent such asmethanesulfonyl chloride or p-toluenesulfonyl chloride in the presenceof a base such as, but not limited to DIPEA or triethylamine in asuitable solvent at a suitable reaction temperature. Suitable solventsfor use in the above reaction included, but were not limited to,chlorinated solvents such as dichloromethane, 1,2-dichloroethane and thelike, ethers such THF, diethylether and the like, DMF and acetonitrile.If desired, mixtures of these solvents were used. The preferred solventswere THF and dichloromethane. The above process was carried out attemperatures between about −78° C. and about 120° C. Preferably, thereaction was carried out between 40° C. and about 95° C. The aboveprocess to produce compounds of the present invention was preferablycarried out at about atmospheric pressure although higher or lowerpressures were used if desired.

Compounds of Formula X-W were prepared from compounds of Formula XI-W.In a typical preparation of a compound of Formula X-W, a compound ofFormula XI-W was reacted with a reducing reagent such as, but notlimited to, sodium borohydride, lithium borohydride or lithium aluminumhydride in a suitable solvent at a suitable reaction temperature.Suitable solvents for use in the above reaction included, but were notlimited to, ethers such THF, diethylether and the like, and alcoholssuch as ethanol, methanol, isopropanol and the like. If desired,mixtures of these solvents were used. The preferred solvents were THFand methanol. The above process was carried out at temperatures betweenabout −78° C. and about 120° C. Preferably, the reaction was carried outbetween 40° C. and about 95° C. The above process to produce compoundsof the present invention was preferably carried out at about atmosphericpressure although higher or lower pressures were used if desired.

Compounds of Formula XI-W were prepared from compounds of Formula XI-W.In a typical preparation of a compound of Formula XI-W, a compound ofFormula IX-W was reacted with an oxidizing reagent such as, but notlimited to, selenium dioxide, manganese dioxide, potassium permanganateand the like, in a suitable solvent at a suitable reaction temperature.Suitable solvents for use in the above reaction included, but were notlimited to, chlorinated solvents such as dichloromethane,1,2-dichloroethane and the like, water, acetic acid and sulfolane. Ifdesired, mixtures of these solvents were used. The above process wascarried out at temperatures between about −78° C. and about 120° C.Preferably, the reaction was carried out between 40° C. and about 95° C.The above process to produce compounds of the present invention waspreferably carried out at about atmospheric pressure although higher orlower pressures were used if desired.

Those skilled in the art will appreciate that compounds of Formula IX-Wcan be made by routes disclosed in the literature, for example as inBulletin de la Societe Chimique de France, (1973), (6)(Pt. 2), 2126.

Compounds of Formula I-AQ and/or their precursors may be subjected tovarious functional group interconversions as a means to access somefunctionalities that may not be introduced directly as a result ofincompatible chemistries. Examples of such functional groupmanipulations applicable to compounds of Formula I-AQ and theirprecursors are similar, but not limited to, those described in Schemes16-27, 34 and 35 that related to compounds of Formula I-AA, I-P, I-P′,I-Q, I-R, I-AB and I-AC.

Experimental Procedures 8-Chloro-3-cyclobutyl-imidazo[1,5a]pyrazine

This compound was prepared using procedures analogous to that describedfor trans-methyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate and itsprecursor trans-methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate,using cyclobutanecarboxylic acid in place of4<methoxycarbonyl)cyclohexanecarboxylic acid.

8-Chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine

8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and NIS(1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Arfor 6 h. The reaction was diluted with DCM (˜400 mL), washed (H₂O,brine), dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the crude material by flash chromatography on silica gel(50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the titlecompound as a pale yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d,J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintetd, J=1.2 Hz, 8.4 Hz,1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100)[MH⁺]; HPLC: t_(R)=3.38 min (OpenLynx, polar_(—)5min).

3-Cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine

A Parr bomb containing8-chloro-3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazine (759 mg, 2.3 mmol) inIPA (100 ml) was saturated with NH₃(g) for 5 min at 0° C. then sealedand heated at 115° C. for 38 h. The reaction mixture was thenconcentrated under reduced pressure, partitioned between DCM (200 mL)and H₂O (50 mL) and extracted with DCM (50 mL). Combined organicfractions were washed with brine, dried (Na₂SO₄) and concentrated underreduced pressure to provide the title compound as a white solid; ¹H NMR(400 MHz, CDCl₃) δ 7.13 (d, J=4.8 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 5.63(br, 2H), 3.73 (quintetd, J=0.8 Hz, 8.4 Hz, 1H), 2.60-2.38 (m, 4H),2.20-1.90 (m, 2H); MS (ES+): m/z 315.9 (100) [MH⁺]; HPLC: t_(R)=1.75 min(OpenLynx, polar-5 min).

7-Cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine

To a suspension of 1H-1,2,4-triazole (1 g, 0.02 mol) in acetonitrile (23mL) was added dropwise phosphoryl chloride (0.6 mL, 0.007 mol) andtriethylamine (3 mL, 0.02 mol) at 0° C. To this mixture was added7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H-one (77 mg, 0.224mmol) and the resulting mixture refluxed overnight. The cooled mixturewas then quenched with excess NH₃ in ^(i)PrOH (pH 8) stirred at rt for30 min. then filtered and the isolated solid washed with DCM. Thefiltrate was concentrated in vacuo and purified by chromatography oversilica gel eluting with 2% MeOH in DCM to afford the7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine. ¹H NMR (400MHz-DMSO-d6) δ 1.14-1.91 (m, 10H), 3.11-3.18 (m, 1H), 6.75 (br.s, 1H),7.84 (s, 1H) 8.42 (bs, 1H); MS (ES+): m/z: 344.01 (100) [MH+]. HPLC:t_(R)=3.10 min (OpenLynx: polar_(—)5 min).

7-Cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one

To a solution of 7-cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (130mg, 0.6 mmol) in DMF (0.6 mL) was added N-iodosuccinimide (700 mg, 0.003mol) and the reaction mixture stirred at 55° C. for 20 h. After thistime the mixture was diluted with water (50 mL) and extracted with EtOAc(4×40 mL). The organic extracts were washed with water (4×40 mL),treated with sodium thiosulfate and brine, dried over Na₂SO₄ andconcentrated in vacuo to afford7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one. ¹H NMR (400MHz-DMSO-d6) δ 1.34-1.37 (m, 3H), 1.52-1.56 (m, 2H), 1.76-1.88 (m, 5H),3.06-3.08 (m, 1H) 7.87 (s, 1H) 11.78 (s, 1H); MS (ES+): m/z: 344.95(100) [MH+]. HPLC: tr=2.95 min (OpenLynx: polar_(—)5 min).

7-Cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

To a suspension of 6-aminomethyl-4H-[1,2,4]triazin-5-one (250 mg, 1.98mmol) in DMF (7.5 mL) was added2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(760 mg, 2.35 mmol), cyclohexanecarboxylic acid (305 mg, 2.38 mmol) andN,N-diisopropylethylamine (1.5 mL, 8.6 mmol). After 1 h acetonitrile (40mL) was added to the mixture followed by dropwise addition of phosphorylchloride (0.28 mL, 3.0 mmol) and the reaction mixture stirred at 55° C.for 1 h. The mixture was then concentrated in vacuo chromatographed oversilica gel eluting with 3% MeOH in DCM, to afford7-cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one. ¹H NMR (400MHz-DMSO-d6) δ 1.24-1.91 (m, 10H), 3.08-3.16 (m, 1H), 7.68 (s, 1H) 7.88(s, 1H) 11.76 (s, 1H); MS (ES+): m/z: 219.24 (100) [MH+]. HPLC:t_(R)=2.44 min (OpenLynx: polar_(—)5 min).

trans-[4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol

trans-[4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol(26.50 g, 67.66 mmol) was charged in a 400 ml steel bomb and wasdissolved in 2M NH₃ in isopropanol (300 mL) and anhydrous THF (10 mL).The reaction mixture was cooled to −78° C. Ammonia gas was bubbledvigorously into the solution for 8 min; then the bomb was tightly sealedand heated to 120° C. for 20 h. The crude reaction mixture wasconcentrated in vacuo, then the reaction residue was taken up withMeOH/CHCl₃, loaded onto silica gel. The mixture was purified by a silicagel glass column chromatography [eluted with 1:1 CH₂Cl₂/EtOAc to 10%˜7 NNH₃ in MeOH/CHCl₃] to afford the desired product as a beige cream whitesolid; MS (ES+): m/z 373.01 (100) [MH⁺], 373.98 (50) [MH⁺2];t_(R)(polar-5min/openlynx) 1.57 min.

trans-[4(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol

trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (18.00g, 67.74 mmol) and N-iodosuccinimide (19.81 g, 88.06 mmol) in anhydrousDMF (360 mL) were stirred at 60° C. under N₂ for 6 h. The reaction wasdiluted with DCM (˜600 mL), washed with water and brine, dried overanhydrous Na₂SO₄ and then concentrated in vacuo. The crude material waspurified by a silica gel flash chromatography (eluted with 1:2 EtOAc/DCMto 1:1 EtOAc/DCM) to obtain the desired product as a pale yellow solid;By ¹H NMR analysis, the product was contaminated with 0.35 eq. ofNIS-impurity. The product was carried onto the next reaction withoutfurther purification; MS (ES+): m/z 391.92 (100) [MH⁺], 393.88 (50)[MH⁺2], 394.89 (10) [MH⁺3]; t_(R)(polar-5 min/openlynx) 2.79 min.

trans-[4(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol

A THF solution (1.00 L) of trans-methyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (29.70 g,101.1 mmol) was cooled to −78° C. and was charged with LAB (1M in TH-F,25-3 mmol, 25.3 mL) dropwise. After 30 min., the reaction mixture wascharged with additional LAH (25.3 mmol) at −78° C. and then, allowed tostir at −78° C. for 1.5 h. The reaction was slowly warmed up to rt andstirred for additional 30 min. Ethyl acetate, Na₂SO₄.10H₂O, and silicagel were added to the reaction mixture and concentrated in vacuo to givean orange solid. The crude mixture was purified by a silica gel glasscolumn chromatography (eluted with 2:3 EtOAc/DCM to 100% EtOAc) toobtain the title compound as a slightly yellow-tinted white solid; ¹HNMR (CDCl₃, 400 MHz) δ 1.14-1.30 (m, 2H), 1.61-1.75 (m_(c), 1H), 1.84(dd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.98-2.13 (m, 4H), 2.19 (s, br,—OH), 2.94 (tt, J=11.6, 3.2 Hz, 1H), 3.56 (d, J=6.0 Hz, 2H), 7.31 (d,J=5.2 Hz, 1H), 7.64 (dd, J=5.2, 1.2 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H); MS(ES+): m/z 266.21/268.17 (100/89) [MH⁺]. HPLC: t_(R)=2.38 min (OpenLynx,polar_(—)5 min). MS (ES+): m/z 266.21 (100) [MH⁺], 268.17 (80) [MH⁺2},289.18 (20) [MH⁺3]; t_(R)(polar_(—)5 min/openlynx) 2.36 min.

General Procedure for the Hydrolysis of Carboxylic Esters

To a solution/slurry of the carboxylic ester (30.17 mmol) in ethanol(200 mL) was added 3.0 M of sodium hydroxide in water (15.1 mL) and themixture was stirred at 40° C. for 4 h. The solvent was removed underreduced pressure at 40° C. and to the residue was added water (10 mL)and ethanol (10 ml) and the slurry was filtered. The filter cake waswashed with ethanol (2×10 mL) and dried under vacuum to yield the sodiumsalt. For the isolation of the free acid, water was added to this saltand the slurry was acidified with formic acid, stirred for 10 min at RTand filtered. The filter cake was washed with water followed by ethanolto yield the carboxylic acid.

trans-Methyl 4(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate

trans-Methyl4-({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)-cyclohexanecarboxylate(29.00 g, 93.02 mmol) was dissolved in anhydrous acetonitrile (930 mL)and anhydrous DMF (9 mL) and heated at 55° C. under nitrogen for 3 h.The reaction mixture was concentrated in vacuo, then, the solid residuewas taken up in DCM, then, basified to pH 10 with 2M ammonia inisopropanol. The mixture was concentrated in vacuo, re-dissolved in DCM,and then loaded onto TEA-basified silica gel. The crude product waspurified by a silica gel column chromatography (eluted with 2:3EtOAc/DCM) to obtain the title compound as a yellow powder; ¹H NMR(CDCl₃, 400 MHz) δ 1.63 (ddd, J=13.2, 13.2, 13.2, 3.2 Hz, 2H), 1.85(ddd, J=13.2, 13.2, 13.2, 2.8 Hz, 2H), 2.10 (dd, J=14.4, 3.2 Hz, 2H),2.19 (dd, J=14.0, 3.2 Hz, 2H), 2.46 (t, J=12.4, 3.6 Hz, 1H), 2.96 (tt,J=116, 3.2 Hz, 1H), 3.70 (s, 3H), 7.33 (dd, J=5.2, 1.2 Hz, 1H), 7.61,J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z 294.17/296.14 (100/86) [MH⁺].HPLC: t_(R)=2.85 min (OpenLynx, polar_(—)5 min).

trans-Methyl4({[(3-chloropyrazin-2-yl)methyl]amino}carbonyl)cyclohexanecarboxylate

A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid(15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under anitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixturewas cooled to rt, then, (3-chloropyrazin-2-yl)methylaminebis-hydrochloride salt (16.00 g, 73.91 mmol) and DIPEA (31.52 g, 244.00mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, thereaction was concentrated in vacuo. The crude reaction mixture waspurified by a silica gel glass column chromatography (eluted with 3:2DCM/EtOAc) to obtain the pure desired product as a slightly yellowishcreamy white powder, ¹H NMR (CDCl₃, 400 MHz) δ 1.43-1.65 (m, 4H),2.01-2.14 (m, 4H), 2.25 (tt J=12.0, 36 Hz, 1H), 2.34 (tt, J=11.6, 3.2Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, —NH),8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12(84132) [MH⁺]; HPLC: t_(R)=2.44 min (OpenLynx, polar_(—)5 min).

[3-(8-Amino-1-iodoimidazo[1,5a]pyrazin-3-yl)cyclobutyl]methanol

[3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol (6.9g) in i-PrOH (200 mL) was saturated with NH_(3(g)), by passing a slow aslow stream of ammonia for 10 min at −20° C., and then heated in a Parrbomb at 110° C. for 2 d. The reaction mixture was then cooled to rt,filtered through a sintered glass and the solid residue and the Parrvessel were rinsed with i-PrOH several times. The filtrate wasconcentrated under reduced pressure to provide an orange solid stillcontaining NH₄Cl. The material was taken up into refluxing MeCN (250 mL)and filtered hot. The step was repeated with another portion of hot MeCN(200 mL). The combined MeCN filtrates were concentrated under reducedpressure to give the title compound as an orange solid; HPLC:(polar5min) 0.53 and 1.51 min; MS (ES+): 345.1 (100, M⁺+1); ¹H NMR (400MHz, DMSO-d6) δ 7.50 (d, J=5.2 Hz, 1H), 7.44 (d, J=5.2 Hz, 0.27H, minorisomer), 6.95 (d, J=5.2 Hz, 1.29H overlapped with the minor isomer) 6.63(br, 2H), 4.61 (t, J=5.2 Hz, 0.27H, minor isomer), 4.52 (t, J=5.2 Hz,1H), 3.69 (quintet J=5.6 Hz, 0.32H, minor isomer), 3.54 (quintet, J=5.6Hz, 1H), 2.52-2.25 (m, 4H), 2.10-2.00 (m, 1H).

[3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)cyclobutyl]-methanol

To a solution of NIS (6.31 g, 28.0 mmol) in anh DMF (100 mL) under Arwas added dry [3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol(6.67 g) dissolved in anh DMF (30 mL). The flask containing[3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol was rinsedwith another portion of anh DMF (20 mL) and the rinse was added to thereaction mixture. The reaction was heated to 60° C. (rt→60° C.˜30 min)and the stirred at this temperature for 3 h. The mixture was then cooledto rt, partitioned between 1M aq Na₂S₂O₃ (60 ml), brine (60 mL) and DCM(160 mL). The aq layer was extracted with DCM (3×100 mL). The combinedorganics were dried (Na₂SO₄), concentrated under reduced pressure andpurified by flash chromatography on SiO₂ (0-8% MeOH in DCM) to provide amaterial, homogenous by UV on both TLC and HPLC, still containing DMF.The material was dissolved in DCM (200 mL) and washed with water (3×40mL), dried (Na₂SO₄) and concentrated under reduced pressure to providethe title compound as a pale yellow solid; HPLC (polar 5 min) 2.52 min;MS (ES+): m/z (rel. int.) 364.0 (100, M⁺ +1); ¹H NMR (400 MHz, CDCl₃) δ7.59 (d, J=4.8 Hz, 1H), 7.49 (d, J=4.8 Hz, 0.22H, minor isomer), 7.29(d, J=4.8 Hz, 1H), 7.28 (d, J=5.2 Hz, 0.23H, minor isomer), 3.83-3.80(m, 0.7H), 3.72-3.62 (m, 3H), 2.75-2.55 (m, 4H), 2.42-2.32 (m, 1-2H).

[3-(8-Chloro-imidazo[1,5-a]pyrazin-3-yl)cyclobutyl]-methanol

To a solution of8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (4.48 g, 20.4mmol) in anh THF (255 mL) at −78° C. under Ar, 9-BBN (61.2 mL, 0.5M inTHF, 30.6 mmol) was added dropwise over 8 min (a suspension). Thecooling bath was replaced with ice-H₂O and the reaction was allowed towarm slowly to rt. After being stirred for 17 h, H₂O (100 mL) was addedfollowed by, after ˜5 min, NaBO₃.H₂O (12.2 g, 122.3 mmol) added in onelot. The reaction was stirred at rt for 5 h and then filtered throughCelite. The Celite and residual solids were washed with DCM and EtOAc.The filtrate was concentrated under reduced pressure to yield an aqsolution, which was saturated with NaCl and extracted with EtOAc (3×).The extracts were dried (Na₂SO₄) and concentrated under reduced pressureto yield a light yellow oil which was purified by flash chromatographyon SiO₂ (9:1 DCM:MeOH) to afford the title compound as a light yellowoil; HPLC: t_(R) (mass-directed HPLC, polar 7 min) 2.52 min; MS (ES+):238.0. The addition may be carried out at 0° C. Suspension quicklyclears up after the exchange of cooling baths. The final productcontained 1,5-cis-octanediol derived from 9-BBN. Based on ¹H NMRestimated roughly to be 66% target material and 33% of the byproduct.The crude product was taken onto next step crude, stereoselectivity ofthe product was 4-5:1 as judged by ¹H NMR.

(8-Chloro-3-(3-methylene-cyclobutyl)-imidazo[1,5-a]pyrazine)

3-Methylene-cyclobutanecarboxylic acid(3-chloro-pyrazin-2-ylmethyl)-amide (52.1 g, 219.2 mmol) was dissolvedin 1.0 L of anhydrous MeCN. Followed by the addition of DMF (1.0 mL) andPOCl₃ (100 mL, 1.09 mol). The reaction was heated to 55° C. for 30 min.with a slow N₂ bubbling the reaction. The reaction was then concentratedin vacuo, basified with cold 2.0M NH₃ in IPA with CH₂Cl₂. The IPA/CH₂Cl₂was concentrated in vacuo and the salts were dissolved with minimalwater and extracted with CH₂Cl₂ (4×). The organic layers where combinedand washed with sat. NaHCO₃ (1×), dried over sodium sulfate, filteredand concentrated in vacuo. The crude product was purified via silica gelcolumn chromatography [eluting with 2:1 Hex:EtOAc] to yield the titlecompound as a light yellow solid; ¹H NMR (400 MHz, CDCl₃) δ 3.24-3.30(4H, m), 3.78-3.85 (1H, m), 4.89-4.94 (2H, m), 7.33 (1H, d, J=4.99 Hz),7.53 (1H, d, J=5.09 Hz), 7.82 (1H, s); MS (ES+): m/z 220.28/222.30(100/80) [MH⁺]; HPLC: t_(R)=2.87 min (OpenLynx, polar_(—)5 min).

3-Methylene-cyclobutanecarboxylic acid (3-chloropyrazin-2-ylmethyl)amide

C-(3-Chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g, 4.62 mmol),N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (1.31 g, 6.47 mmol,1.4 eq.), 4-dimethylamino pyridine DMAP) (0.141 g, 1.15 mmol, 0.25 eq.),and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9 mmol, 3.0 eq.)were dissolved in anhydrous CH₂Cl₂ (25 mL). To this solution, a solutionof 3-methylenecyclobutanecarboxylic acid (0.622 g, 5.54 mmol, 1.2 eq.)in anhydrous CH₂Cl₂ (25 mL) was added under N₂ and the reaction wasallowed to stir overnight at rt. Reaction mixture was concentrated invacuo and the resulting residue was dissolved in EtOAc, washed withwater (2×), NaHCO₃ (1×), water (1×), and brine (1×), dried over Na₂SO₄,filtered, and concentrated in vacuo, giving crude title compound, as abrown oil. The crude material was purified by chromatography on silicagel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with EtOAc:Hex10%→20%→40%→70%], affording the title compound as a pale yellow solid.Additionally, the title compound could be prepared by the followingroute: 1,1′—Carbonyldiimidazole (CDT) (0.824 g, 5.08 mmol, 1.1 eq.) and3-methylenecyclobutanecarboxylic acid (0-570 g, 5.08 mmol, 1.1 eq.) weredissolved in anhydrous THF (12 mL) and allowed to stir at 60° C. for 2h. A solution of C-(3-chloropyrazin-2-yl)-methylamine bis-HCl (1.0 g,4.62 mmol) and diisopropylethylamine (DIPEA) (2.42 mL, 1.79 g, 13.9mmol, 3.0 eq.) in anhydrous CH₂Cl₂ (13 mL) was added to the acid mixtureand the reaction was allowed to stir at 60° C., under N₂, overnight. Thereaction mixture was concentrated in vacuo and the resulting residue wasdissolved in EtOAc, washed with NaHCO₃ (2×) and brine (1×), dried overNa₂SO₄, filtered, and concentrated in vacuo, giving crude titlecompound, as a brown oil. The crude material was purified bychromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge,eluting with EtOAc:Hex 10%→20%→40%→70%], affording the title compound asa pale yellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 2.86-2.96 (m, 2H),3.03-3.19 (m, 3H), 4.72 (dd, J=4.4, 0.8 Hz, 2H), 4.79-4.84 (m, 2H), 6.78(s, —NH), 8.32-8.34 (m, 1H), 8.46 (d, J=2.8 Hz, IRS); MS (ES+): m/z238.19 (90) [MH⁺]; HPLC: t_(R)=2.67 min (OpenLynx, polar_(—)7 min).

3-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanol

In a Parr pressure reactor3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanol (4.159 g,0.0119 mol) was dissolved with 2.0M ammonia in isopropyl alcohol (40mL). The mixture was cooled to −20° C. and saturated with ammonia. Thereaction was heated at 110° C. for 63 h at which point it was cooled andconcentrated in vacuo. The crude product was purified using HPFC Jones25 g silica gel column eluting with 5-8% MeOH:CH₂Cl₂ to yield the titlecompounds; MS (ES+): m/z 330.88 (100) [MH⁺], 331.89 (10) [MH⁺⁺]; HPLC:t_(R)=0.48 min (OpenLynx, polar_(—)5 min); ¹H NMR (CDCl₃, 400 MHz) δ2.55-2.76 (m, 2H) 3.06-3.22 (m, 2H) 3.32-3.50 (m, 1H) 4.51-4.69 (m, 1H)6.15 (br.s., 2H) 7.24 (d, J=5.05 Hz, 1H) 7.39 (d, J=5.05 Hz, 1H).

3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanol

3-(8-Chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (5.0 g, 14mmol) was dissolved in a 1:1 mixture of methanol (35.0 mL) and CH₂Cl₂(35.0 mL). To the solution mixture sodium tetrahydroborate (560 mg, 14.0mmol) was added slowly, gas evolution was observed. After 4.5 h at rtunder nitrogen, the reaction was concentrated in vacuo. The crude mixwas dissolved in EtOAc and washed with water. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified using HPFC Jones 50 gram silica gel column elutingwith 50% EtOAc:Hex to 100% EtOAc, to yield the title compound as a lightyellow solid; MS (ES+): m/z 349.81 (100) [MH⁺], 351.50 (30) [MH⁺⁺⁺];HPLC: t_(R)=2.49 min (OpenLynx, polar_(—)5 min); ¹H NMR (CDCl₃, 400 MHz)2.41-2.54 (m, 2H) 2.78-3.05 (m, 1H) 3.12-3.32 (m, 1H) 4.08-4.75 (m, 1H)5.30 (s, 1H) 7.31 (d, J=5.05 Hz, 1H) 7.57 (d, J=4.80 Hz, 1H)

1-{4-[3-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]piperazin-1-yl}ethanone

1-{4-[3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]piperazin-1-yl}ethanone(13.2 g, 0.029 mol) was dissolved in isopropyl alcohol (100 mL) into aParr pressure reactor. The vessel was cooled to −78° C. and saturatedwith ammonia gas and sealed. The reaction was heated for 19 h at 110°C., at which point the reaction was cooled and the solvent concentratedin vacuo. The crude product was purified via silica gel chromatographyeluting with 5-10% MeOH (7M NH₃): CH₂Cl₂ to yield the title compounds asan off white solid; MS (ES+): m/z 440.89 (100) [MH⁺], 441.89 (20)[MH⁺⁺]; HPLC: t_(R)=0.46 min (OpenLynx, polar_(—)5min); ¹H NMR (CDCl₃,400 MHz) δ 2.09 (s, 3H) 2.28-2.48 (m, 6H) 2.54-2.71 (m, 2H) 2.80-2.99(m, 1H) 3.27-3.43 (m, 1H) 3.43-3.54 (m, 2H) 3.56-3.70 (m, 2H) 7.02 (d,#5.05 Hz, 1H) 7.16 (d, J=5.05 Hz, 2H).

1-{4-[3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]piperazin-1-yl}ethanone

Into a RBF 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanone(1.00 g, 0.0029 mol) and sodium triacetoxyborohydride (1.30 g, 0.006mol) were dissolved in 1,2-dichloroethane (65.0 mL) and a solution of1-acetylpiperazine (0.39 g, 0.003 mol) in 1,2-dichloroethane was addedto the reaction. The reaction mixture was stirred at rt for 2 h. Thecrude product was concentrated in vacuo and the dissolved in CH₂Cl₂(25.0 mL) and washed with saturated NaHCO₃ solution (1×40 mL). Theproduct was dried with sodium sulfate and concentrated in vacuo to yielda light yellow solid; MS (ES+): m/z 459.84 (100) [MH⁺], 461.80 (40)[MH⁺⁺⁺]; HPLC: t_(R)=1.81 min (OpenLynx, polar_(—)5 min); ¹H NMR (CDCl₃,400 MHz) δ 2.04-2.15 (m, 3H) 2.26-2.50 (m, 6H) 2.55-2.72 (m, 2H)2.83-2.99 (m, 1H) 3.29-3.52 (m, 3H) 3.56-3.67 (m, 2H) 7.29 (d, 1H) 7.58(d, 1H).

(1-Iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine)

A solution of 2N ammonia in isopropyl alcohol (350 ml) and THF (30 mL,0.4 mol) was added to8-chloro-1-iodo-3-[3-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazine(19.91 g, 0.04612 mol) in a Parr bomb and cooled to −78° C. Ammonia wasbubbled into the solution for 8-10 min. The bomb was sealed, stirred andheated to at 110° C. over 3 d. The solvent was then evaporated in vacuoand purified by flash silica gel chromatography (wetted with CHCl₃,dried loaded with silica, and eluted with 8% (7N NH₃) MeOH in CHCl₃),which afforded the title compound; ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (1H,d, J=5.01), 7.16 (1H, d, J=6.25), 5.83 (2H, s), 3.49 (1H, m), 3.06 (1H,m), 2.76 (4H, m), 2.64 (8H, m), 2.46 (3H, s); MS (ES+): m/z412.89/413.91 (50/10) [MH⁺]; HPLC: t_(R)=0.31 min. (OpenLynx, polar_(—)5min.).

(8-Chloro-1-iodo-3-[3-(4-methylpiperazin-1-yl)cyclobutyl]imidazo[1,5-a]pyrazine)

1-Methyl piperazine (5.75 mL, 0.0514 mol) in 1,2-dichloroethane (1096.7mL, 13.892 mol) was added to3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (17.00 g,0.04892 mol) and sodium triacetoxyborohydride (21.8 g, 0.0978 mol). Thereaction stirred at rt for 3 h. The reaction was concentrated, dissolvedin CH₂Cl₂, and then washed with saturated NaHCO₃ solution and brine. Theproduct was dried over sodium sulfate, filtered, and concentrated invacuo. The product was flushed through a quick silica gel plug (wettedwith 100% CHCl₃, eluted with 8% (7N NH₃) MeOH in CHCl₃), to afford thetitle compound; ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (1H, d), 7.30 (1H, d),3.42 (1H, m), 2.94 (1H, m), 2.65 (4H, m), 2.44 (8H, m), 2.32 (3H, s); MS(ES+): m/z 431.85/433.87 (100/45) [MH⁺]; HPLC: t_(R)=1.82 min.(OpenLynx, polar_(—)5 min.).

3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (1.95 g, 8.80 mmol)in anhydrous THF (77.78 mL) at −78° C. under an atmosphere of nitrogenwas treated slowly with a 3.0 M solution of methylmagnesium chloride inTHF (5.9 mL). The solution stirred for 3 hr at −78° C. then quenchedwith 40 mL of semi-saturated aqueous NH₄Cl (NH₄Cl dilution in 1:1mixture with water) at −78° C. and allowed to warn up to rt. The mixturewas then extracted with EtOAc (3×40 mL) and the combined extracts washedwith brine (30 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude solid was purified by chromatographyover silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCMto afford desired product. ¹H-NMR (400 MHz, CDCl₃) δ ppm 1.54 (s, 3H),2.74-2.60 (m, 4H), 3.75-3.39 (m, 1H), 7.35 (d, J=5.04 Hz, 1H), 7.71 (d,J=5.00 Hz, 1H) and 7.86 (s, 1H). MS (ES+): m/z 238.15 and 240.17 [MH⁺].

3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (2.20 g,9.26 mmol) and NIS (2.71 g, 12.0 mmol) were dissolved in DMF (36.6 mL,0.472 mol) and stirred at 60° C. for 4 h. The mixture was thenconcentrated in vacuo and the residue reconstituted in EtOAc (100 mL).This solution was washed with sodium bicarbonate (2×20 mL) and thesewashes back-extracted with EtOAc (2×20 mL). The organic layers werecombined, dried with sodium sulfate, filtered and concentrated in vacuo.The crude solid was purified by chromatography over silica gel elutingwith 1:1 EtOAc:hexanes to afford desired product. ¹H-NMR (400 MHz,CDCl₃) δ ppm 1.53 (s, 3H), 2.72-2.59 (m, 4H), 3.37-3.29 (m, 1H), 7.32(d, J=4.91 Hz, 1H) and 7.60 (d, J=4.96 Hz, 1H). MS (ES+): m/z 363.95 and365.91 [MH⁺].

3-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

A solution of 2M ammonia in isopropanol (80 mL) and THF (5 mL) was addedto 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol(2.77 g, 7.62 mmol) in a Parr pressure reactor. The mixture was cooledto at −78° C. then ammonia gas was bubbled into the solution for 4-6min. The reactor was sealed then heated at 110° C. for 15 h. The solventwas then removed in vacuo and the residue purified by chromatographyover silica gel eluting with 7% MeOH in DCM to afford desired product.¹H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 3H), 2.32-2.51 (m, 4H),3.33-3.52 (m, 1H), 6.61 (br.s., 2H), 7.03 (d, J=5.05 Hz, 1H) and 7.62(d, J=5.05 Hz, 1H).

(3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanone)

A solution of3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol(4.08 g, 0.011 mol) in THF (120 mL) and water (40 mL) was charged withsodium periodate (2.8 g, 0.013 mol) at 0° C. The reaction warmed to rtand stirred for h. The reaction mixture was diluted with ethyl acetateand then washed with brine. The organic phase was dried over Na₂SO₄,filtered, and concentrated in vacuo to afford the title compound as ayellow solid; ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (1H, d, J=4.94), 7.32 (1H,d, J=4.98), 3.64 (5H, m); MS (ES+): m/z 347.82 and 349.85 [MH⁺]; HPLC:t_(R)=2.89 min. (OpenLynx, polar_(—)5 min.).

3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol

Under inert atmosphere N-iodosuccinimide (3.6 g, 0.016 mol) and3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol (3.16g, 0.012 mol) were dissolved in N,N-dimethylformamide (30 mL) and heatedat 60° C. for 3.0 h. The reaction mixture was then concentrated in vacuoto a dark oil and purified by HPFC Jones 20 g silica gel column, elutingwith 5% MeOH:CH₂Cl₂ to yield a light brown fluffy solid which wastriturated with diethyl ether and hexanes to afford the title compound;MS (ES+): m/z 379.85 and 381.80 [MH⁺]; HPLC: t_(R)=2.30 min (OpenLynx,polar_(—)5 min).

3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)-1-hydroxymethylcyclobutanol

To a THF solution (170 mL) of8-chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine (3.1 g, 14mmol), water (18 mL), 50% N-methylmorpholine-N-oxide in water (3.2 mL)and potassium osmate, dehydrate (200 mg, 0.70 mmol) were added and thereaction was allowed to stir at rt for 4 h. Sodium sulfite (8.0 g, 70.0mmol) was added to the reaction mixture and allowed to stir for 30 minat which point the reaction was concentrated in vacuo. The crude productwas extracted from the aqueous with EtOAc. The organics were washed withbrine and the combined aqueous washes were back extracted with EtOAc(5×50 μL). The combined organics were dried over sodium sulfate,filtered, and concentrated in vacuo to yield the title compounds as asticky tan/off-white solid; MS (ES+): m/z 254.17 (100) [MH⁺], 256.19(50) [MH⁺⁺⁺]; HPLC: t_(R)=1.95 min (OpenLynx, polar_(—)5 min).

3-Methylene-cyclobutanecarboxylic Acid

To a solution of 3-methylenecyclobutanecarbonitrile (100.0 g, 1.042 mol)in ethanol (1.00 L) and water (1.00 L) was added potassium hydroxide(230.0 g, 4.2 mol). The resulting mixture was heated at reflux for 7 hrthen the EtOH was removed in vacuo and the solution was cooled to 0° C.and acidified with (300.0 mL) of conc. HCl to pH=1. The mixture wasextracted with diethyl ether (4 ×1 L) and the combined organic phaseswere dried over sodium sulfate, filtered and concentrated in vacuo toyield desired product. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.64-3.44 (m, 5H),4.60-4.98 (m, 2H) and 10.64 (br. s., 1H).

Ethyl 3-methylenecyclobutanecarboxylate

Iodoethane (7.5 mL, 93.0 mol) was added at rt to a mixture of3-methylenecyclobutanecarboxylic acid (10.0 g, 80.0 mmol) and cesiumcarbonate (56.0 g, 170.0 mmol) in anhydrous N,N-dimethylformamide(500.00 mL) under an atmosphere of nitrogen. The reaction was stirredfor 16 hr then partitioned between diethyl ether (1 L) and brine (1 L).The aqueous layer was extracted with diethyl ether (3×500 mL) and thecombined organic phases washed with water (2×1 L), dried over sodiumsulfate, filtered and concentrated in vacuo to yield desired product ¹HNMR (400 MHz, CDCl₃) δ ppm 1.26 (t, 3H), 2.71-3.27 (m, 5H), 4.15 (q,J=7.07 Hz, 2H) and 4.53-4.96 (m, 2H).

N-[(3-chloropyrazin-2-yl)methyl]-3-methylenecyclobutanecarboxamide

1,1′—Carbonyldiimidazole (CDI) (8.24 g, 50.81 mmol) and3-methylenecyclobutanecarboxylic acid (5.70 g, 50.81 mmol) weredissolved in anhydrous THF (100 mL) and allowed to stir at 60° C. for 4h. A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride(10.0 g, 46.19 mmol) and diisopropylethylamine DIPEA) (32.30 mL, 184.76mmol) in anhydrous CH₂Cl₂ (150 mL) was added to the mixture and thereaction was allowed to stir at rt for 24 h. The mixture wasconcentrated in vacuo, the residue dissolved in EtOAc and the resultingsolution washed with saturated NaHCO₃ (aq.) water H₂O and Brine. Thecombined organic layers were dried over sodium sulfate, filtered andconcentrated in vacuo to afford crude product, which was purified bychromatography over silica gel eluting with 50-70% EtOAc/hexane to yielddesired product. ¹H NMR (400 MHz, CDCl₃) δ ppm 2392-2.94 (2H, m),3.05-3.14 (2H, m), 4.60 (2H, d, J=4.24 Hz), 4.80-4.84 (2H, m), 6.75 (1H,brs), 8.33 (1H, d, J=4.22 Hz) and 8.45 (1H, d, J=2.54 Hz). MS (ES+): m/z238 and 240 [MH+].

8-Chloro-3-(3-methylenecyclobutyl)imidazo[1,5-a]pyrazine

N-[(3-Chloropyrazin-2-yl)methyl]-3-methylenecyclobutanecarboxamide (52.1g, 219.2 mmol) in anhydrous MeCN (1.0 L) was treated with DMF (1.0 mL)and POCl₃ (100 mL, 1.09 mol) and the mixture was stirred at 55° C. for30 min. under a gentle stream of N₂. The reaction was then concentratedin vacuo and the residue reconstituted in CH₂Cl₂ and treated with cold2.0 M NH₃ in IPA. This mixture was concentrated in vacuo, water added todissolve the salts, and then extracted with CH₂Cl₂ (4×60 mL). Theorganic layers where combined and washed with sat. NaHCO₃ (1×70 mL)dried over sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified by chromatography over silica gel eluting with 2:1hexane:EtOAc to yield desired product. ¹H NMR (400 z, CDCl₃) δ ppm3.24-3.30 (4H, m), 3.78-3.85 (1H, m), 4.89-4.94 (2H, m), 7.33 (1H, d,J=4.99 Hz), 7.53 (1H, d, J=5.09 Hz) and 7.82 (1H, s). MS (ES+): m/z220.28 and 222.30 [MH+].

C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride

A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0g, 36.5 mmol) in anhydrous CH₂Cl₂ (200 mL) was charged with hydrazine(2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N₂ atmosphere. After2.5 h, MeOH (30 mL) was added and the reaction was heated until thesolution was homogenous. The reaction mixture was allowed to stir for 19h. The white ppt that had formed (2,3-dihydrophthalazine-1,4-dionebyproduct), was filtered off and washed several times with ether. Theclear filtrate was concentrated in vacuo and the concentrate wasdissolved in EtOAc and filtered again to remove white ppt. All solventwas removed, giving a yellow oil, which was dissolved into EtOAc andether and charged with HCl (g). The title compound, a pale yellow solid,instantly precipitated. The title compound was dried in a 40° C. ovenfor 72 h, affording the title compound, as a dark yellow solid; ¹H NMR(400 MHz, CD₃OD) δ 4.55 (2H, s), 8.27 (1H, d, J=2.52 Hz), 8.54 (1H, d,J=2.56 Hz); MS (ES+): #m/z 143.96/145.96 (100/60) [MH⁺]; HPLC:t_(R)=0.41 min (OpenLynx, polar_(—)7 min).

1-{[(3-Oxocyclobutyl)carbonyl]oxy}pyrrolidine-2,5-dione

Into a 5 L reactor equipped with a nitrogen flow and an overhead stirrerwas added N-hydroxysuccinimide (250.0 g, 2.172 mol) and3-oxo-cyclobutanecarboxylic acid (248 g, 2.17 mol). Ethyl acetate (3.4L) was added and the reaction was cooled to 16° C. A solution of 25% DCCin EtOAc (2.17 mol) was added slowly via an addition funnel to thereaction mixture over 7 minutes then the mixture was then heated at 45°C. After 2 h, the mixture was filtered and the filtrate was washed oncewith EtOAc (1 L×1) and evaporated to dryness in vacuo to afford thedesired product. ¹H NMR (400 MHz DMSO-d6) δ 2.83 (bs, 4H), 3.30-3.39 (m,2H), 3.52-3.60 (m, 2H) and 3.67-3.73 (m, 1H).

3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone

Into a round bottom 1-neck flask (5 L), 3-oxo-cyclobutanecarboxylic acid2,5-dioxo-pyrrolidin-1-yl ester (217.2 g, 0.937 mol),C-(3-chloro-pyrazin-2-yl)-methylamine hydrochloride salt (153.3 g, 0.852mol), and THF (760 mL) were added. A solution of 10% NaHCO3 (1.07 kg)was then added and after 20 min, the layers were allowed to separate andthe aqueous layer was removed. The aqueous layer was back extracted withEtOAc (1×700 mL, 1×300 mL). The combined organics were washed with brine(350 mL), dried over MgSO₄, filtered, and concentrated in vacuo toprovide the title compound. This solid was resuspended in ethyl acetate(915 mL) and DMF (132 mL) and the solution was put under an atmosphereof nitrogen and cooled to 10.5° C. Phosphorus oxychloride (159 mL, 1.70mol) was then added over 15 minutes and the reaction was allowed to stirfor 45 min. The reaction solution was then poured slowly into a 22%aqueous Na₂CO₃ solution at 10° C. Water (1 L) was added and the layerswere allowed to separate. The organic layer was removed and the aqueouswas back extracted with EtOAc (1×1 L, 1×0.5 L). The combined organicphases were dried over MgSO₄, filtered, and concentrated in vacuo untilabout 0.5 L of solvent remained. Heptane was added and the slurry wasconcentrated in vacuo until most of the EtOAc was removed. The resultantslurry was filtered to give desired product. ¹H NMR (400 Adz, CDCl₃) δ3.59-3.68 (m, 2H), 3.72-3.79 (m, 2H), 3.86-3.94 (m, 1H), 7.40 (d, 1H,J=5.2 Hz), 7.60 (d, 1H, J=5.2 Hz) and 7.85 (s, 1H).

3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone

3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (47.7 g, 215 mmol)was dissolved in DMF (200 mL) under an atmosphere of nitrogen and cooledto 4° C. N-Bromosuccinimide (40.3 g, 226 mmol) was dissolved in DMF (140mL) and slowly added to the reaction mixture. After 5 min, water (400mL) was added and the resulting solid isolated by filtration and washedwith solid with water to give the title compound. ¹H NMR (DMSO-d6, 400MHz): δ 3.45-3.53 (m, 2H), 3.58-3.67 (m, 2H), 4.08-4.16 (m, 1H), 7.45(d, 1H, J=5.2 Hz) and 8.30 (d, 1H, J=4.8 Hz).

3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

3-(1-Bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (51.988 g,0.17 mot) in anhydrous THF (550 g, 620 mL) under nitrogen at −78° C. wastreated with a 3.0 M solution of methyl magnesium chloride in THF (130mL, 0.38 mol) over 30 min. The mixture was stirred at −78° C. for 30 minand then the cooling bath was removed and the mixture quenched with 14%NH₄Cl (132 g). EtOAc was added to the aqueous phase and the pH wasadjusted to ˜5 with 20% HCl and the layers separated. The combinedorganic phases were concentrated in vacuo to a slurry and 0.5 L oftoluene was added and the mixture concentrated in vacuo until the EtOAcwas removed. The slurry was heated at reflux until homogeneous thenallowed to coot to provide desired product, which was isolated byfiltration and dried in vacuo. ¹H NMR (DMSO-d₆, 400 MHz): δ 1.37 (s,3H), 2.35-2.49 (m, 4H), 3.52 (dddd, 1H, J=9.6, 9.6, 9.6, 9.6 Hz), 5.18(bs, 1H), 7.37 (d, 1H, J=5.2 Hz) and 8.26 (d, 1H, J=5.2 Hz).

3-(Amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

A 35% ammonia solution (132 ml, 2.9 moles) was added to a suspension of3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol(22.0 g, 0.06463 mol) in 2-butanol (81 ml). The mixture was heated at90° C. in a pressure vessel for 15 hr then concentrated to 130 ml,cooled to room temperature and the solid collected by filtration. Thismaterial was washed with water (3×22 mL) and dried at 40° C. undervacuum. To afford the desired product. ¹H NMR (DMSO-d₆, 400 MHz): δ 7.5(d, 1H), 7.0 (d, 1H), 6.6 (bs, 2H), 5.1 (s, 1H), 3.4 (pentet, 1H),2.3-2.4 (m, 4H) and 1.4 (s, 3H).

7-Cyclobutyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-ylamine

To a solution of 1,2,4-triazole (1.28 g, 18.59 mmol) in anhydrouspyridine (10 mL) was added phosphorus oxychloride (POCl₃) (0.578 mL,6.20 mmol) and stirred at rt for 15 min. This mixture was dropwisecharged (3.5 min) with a solution of 7-cyclobutyl-5-iodo-3Himidazo[5,1-f][1,2,4]triazin-4-one (0.653 mg 2.07 mmol) in anhydrouspyridine (14 ml) and stirred for 1.5 h. The reaction mixture was cooledto 0° C. quenched with 2M NH₃ in isopropanol (IPA) until basic thenallowed to reach rt and stirred for an additional 2 h. The reactionmixture was filtered through a fritted Buchner funnel and washed withDCM. The filtrate was concentrated in vacuo and purified bychromatography on silica gel [eluting with 30% EtOAc in DCM] resultingin the title compound as an off-white solid; ¹H NMR (CDCl₃, 400 MHz) δ1.93-2.04 (m, 1H), 2.05-2.18 (m, 1H), 2.35-2.45 (m, 2H), 2.49-2.62 (m,2H), 4.00-4.12 (m, 1H), 7.82 (s, 1H); MS (ES+): m/z 316.08 (100) [MH⁺],HPLC: t_(R)=2.59 min (MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-5-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one

A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789 mg4.15 mmol) and N-iodosuccinimide (NIS, 933 mg, 4.15 mmol) in anhydrousDMF (40 mL) was stirred overnight at rt. An additional 4 eq. of NIS wasadded and reaction was heated to 55° C. for 6 h. The reaction mixturewas concentrated in vacuo and partitioned between DCM and H₂O andseparated. The aqueous layer was washed with DCM (3×) and the combinedorganic fractions were washed with 1M sodium thiosulfate (Na₂S₂O₃) (1×),brine (1×), dried over sodium sulfate (Na₂SO₄), filtered, andconcentrated in vacuo. The solid was triturated with 20% EtOAc in DCMand filtered through a fritted Buchner funnel resulting in the titlecompound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.84-1.96(m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m, 1H), 7.87(s, 1H); MS (ES+): m/z 317.02 (100) [MH⁺], HPLC: t_(R)=2.62 min(MicromassZQ, polar_(—)5 min).

7-Cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

A crude solution of cyclobutanecarboxylic acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide (1.33 g, 6.39 mmol)in phosphorus oxychloride (POCl₃) (10 mL) was heated to 55° C. Thereaction was heated for 2 h then concentrated in vacuo and the crude oilwas cooled to 0° C. in an ice-bath and quenched with 2M NH₃ inisopropanol (IPA) until slightly basic. This crude reaction mixture wasconcentrated in vacuo and was partitioned between DCM and H₂O andseparated. The aqueous layer was extracted with DCM (3×) and thecombined organic fractions were dried over sodium sulfate (Na₂SO₄),filtered and concentrated in vacuo. The crude material was purified bychromatography on silica gel [eluting with 5% MeOH in DCM], resulting inthe title compound as an off-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m,1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z191.27 (100) [MH⁺], HPLC: t_(R)=2.06 min (MicromassZQ, polar_(—)5 min).

Cyclobutanecarboxylic Acid(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide

To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96mmol) and N,N-diisopropylethylamine (DIEA) (0.829 mL, 4.76 mmol) inanhydrous N,N-dimethylforamide (DMF) (20 mL) and anhydrous pyridine (2mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL,3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5h. The reaction mixture was quenched with H₂O (2 mL) and concentrated invacuo and was purified by chromatography on silica gel [eluting with 5%MeOH in DCM (200 mL)→10% MeOH in DCM (800 mL)], affording the titlecompound; ¹H NMR (DMSO-d₆, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m,1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d,2H); 7.97 (brt, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100)[MH⁺], HPLC: t_(R)=1.56 min (MicromassZQ, polar_(—)5 min).

6-Aminomethyl-4H-[1,2,4]triazin-5-one

A slurry of2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione (4 g,15.6 mmol) in DCM/EtOH (1:1) (150 mL) was charged with anhydroushydrazine (1.23 mL, 39.0 mmol) and stirred at rt for 18 h. The reactionmixture was concentrated in vacuo and the off-white solid was trituratedwith warm CHCl₃ and filtered through a fritted funnel. The solid wasthen triturated with hot boiling methanol (MeOH) and filtered through afritted funnel resulting in an off-white solid. The material wastriturated a second time as before and dried overnight resulting in thetitle compound as a white solid, which was taken on to the next stepwithout further purification; ¹H NMR (DMSO-d₆, 400 MHz) δ 3.88 (s, 2H),8.31 (2, 1H); MS (ES+): m/z 127.07 (100) [MH⁺], HPLC: t_(R)=0.34 min(MicromassZQ, polar_(—)5 min).

2-(5-Oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione

A slurry of2-(5-oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)isoindole-1,3-dione(1.0 g, 3.47 mmol) in EtOH (40 mL) was charged with excess Raney Ni (3spatula) and heated to reflux for 2 h. The reaction mixture was filteredhot through a small pad of celite and washed with a hot mixture ofEtOH/THF (1:1) (100 mL) and the filtrate was concentrated in vacuoresulting in the title compound as an off-white solid; ¹H NMR (DMSO-d₆,400 MHz) δ 4.75 (s, 2H), 7.84-7.98 (m, 4H), 8.66 (s, 1H); MS (ES+): m/z257.22 (100) [MH⁺].

2-(5-Oxo-3-thioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylmethyl)indan-1,3-dione

A slurry of 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-oxo-propionic acidethyl ester (20 g, 76.6 mmol) in anhydrous EtOH (300 mL) was chargedwith thiosemicarbazide (6.98 g, 76.6 mmol) in one portion and heated to80° C. for 2 h. The reaction mixture was charged withN,N-diisopropylethylamine (DIEA) (26.7 mL, 76.56 mmol) and heated to 40°C. for 6 h then stirred at Tt for an additional 10 h. The reactionmixture was concentrated in vacuo and solid was triturated with hotEtOH/EtOAc filtered and washed with EtOAc. The solid was dried overnightin a vacuum oven (40° C.) resulting in the title compound as anoff-white solid; ¹H NMR (DMSO-d₆, 400 MHz) δ 4.68 (s, 2H), 7.85-7.95 (m,4H); MS (ES+): m/z 289.2 (100) [MH⁺].

2-[(3-Methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]-1H-isoindole-1,3(2H)-dione

A solution of ethyl3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropanoate [J. Org.Chem., (1985), 50 (1), 91] (4.29 g, 16.4 mmol), acetamidrazonehydrochloride (1.80 g, 16.4 mmol) in anhydrous EtOH (85.8 mL) was heatedto 80° C. for 3 h then cooled to rt and stirred for an additional 16 h.The reaction mixture was filtered through a flitted funnel resulting in3.28 g, (73% yield) of the title compound as a white solid. ¹H NMR (400MHz, DMSO-d6) δ ppm 2.28 (s, 3H), 4.73 (s, 2H) and 7.74-8.12 (m, 4H); MS(ES+): m/z 271.08 [MH+].

6-(Aminomethyl)-3-methyl-1,2,4-triazin-5(4H)-one

A solution of2-[(3-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]-1H-isoindole-1,3(2B)-dione(2.00 g, 7.40 mmol) in DCM (10.0 mL) and EtOH (10.0 mL) was charged withhydrazine (0.58 mL, 181.5 mmol) and stirred at rt for 8 h, then heatedto 45° C. for an additional 16 h. The reaction was charged with anadditional 0.5 equiv of hydrazine (0.116 mL, 3.70 mmol) and heated to45° C. for 4 h. The reaction mixture was allowed to cool to rt thenfiltered through a fritted funnel and the cake was washed with 2portions of cold 1:1 EtOH/DCM (75 mL) and the filtrate was concentratedresulting in 622 mg of a pale yellow solid which was taken on to thenext step without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm2.21 (s, 3H), 3.72 (s, 2H); MS (ES+): m/z 141.06 [MH+].

trans-4-({[(Benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic Acid

trans-4-(Aminomethyl)cyclohexanecarboxylic acid (10.00 g, 0.06361 mol),in a 10% aq solution of NaOH (5.60 g in 55 mL) was cooled to 0° C. andtreated over 15 min with vigorous stirring, with benzyl chloroformate(11 mL, 0.076 mol). After one hour the solution was acidified (1MHCl(aq)) and the resulting the white precipitate collected byfiltration, washed with water and hexane then dried in vacuo ovenovernight to afford 17.23 g of the title compound. ¹H NMR (400 MHz,CDCl₃): δ 0.93-0.99 (m, 2H), 1.38-1.46 (m, 2H), 1.82-1.85 (m, 2H),2.03-2.06 (m, 2H), 2.25 (m, 1H), 3.06 (t, J=5.6 Hz, 2H), 4.83 (m, 1H),5.09 (s, 2H), 7.31-7.36 (m, 5H). MS (ES+): m/z 292 [MH+].

Benzyl[(trans-4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}cyclohexyl)methyl]carbamate

To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt(0.100 g, 0.533 mmol) in DCM (1.35 mL) was addedN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.16 g,0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol),1-hydroxybenzotriazole (0.075 g, 0.56 mmol) andtrans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid(0.21 g, 0.70 mmol). The reaction was stirred at rt overnight thendiluted with DCM, washed with sat. NaHCO₃ (aq) and brine, then driedover Na₂SO₄ and the solvent removed in vacuo. The residue thus isolatedwas chromatographed over silica gel eluting with EtOAc/hexane (1:1) toafford 0.173 g of the title compound. ¹H NMR (400 MHz, CDCl₃): δ1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m,2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br,1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz,1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].

Benzyl{[trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate

To a suspension of benzyl[(trans-4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}cyclohexyl)methyl]carbamate(0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. wasadded slowly POCl₃ (0.082 mL, 0.88 mmol). After stirring at rt for anhour, the mixture was cooled to 0° C. and solid NaHCO₃ was added. Aftera flyer 10 min at 0° C. and 20 min at rt, the mixture was re-cooled to0° C. and water (20 nm) was added. The reaction mixture was extractedwith EtOAc (3×20 mL) and the extracts washed with water (2×30 mL) andbrine (30 mL) and then dried over Na₂SO₄ and concentrated in vacuo toafford 0.096 g of the title compound. ¹H NMR (400 MHz, CDCl₃): δ1.15-1.19 (m, 2H), 1.76-1.87 (m, 3H), 1.93-2.00 (m, 2H), 2.04-2.08 (m,2H), 3.07 (m, 1H), 3.15 (t, J=6.4 Hz, 2H), 4.84 (br, 1H), 5.09 (s, 2H),7.31-7.40 (m, 6H), 7.61 (d, J=4.8 Hz, 1H), 7.79 (s, 1H). MS (ES+): m/z399.26 [MH+].

Benzyl{[trans-4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate

To a solution of benzyl{[trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate(1.49 g, 0.00374 mol) in DMF (0.6 mL) was added NIS (1.0 g, 0.0045 mol).The reaction mixture was stirred at 55° C. overnight then diluted withEtOAc (20 mL), washed with water (2×40 mL) and brine (20 mL), then driedover Na₂SO₄ and concentrated in vacuo. The crude mixture thus isolatedwas chromatographed over silica gel eluting with hexane hexane:EtOAc 1:1to afford 1.7 g of the title compound. MS (ES+): m/z 525.01 [MH+].

Benzyl{[trans-4(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate

A solution of benzyl{[trans-4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate(1.70 g, 0.00324 mol) in IPA (30 mL) was cooled to −78° C., treated witha stream of ammonia gas over 3 min. and then heated at 110° C. in a Parrvessel overnight. The reaction solution was concentrated in vacuo andresidue washed with water to afford 1.37 g of desired product. ¹H NMR(400 MHz, CDCl₃): δ=1.08-1.17 (m, 2H), 1.88 (m, 1H), 1.71-1.81 (m, 2H),1.91-1.94 (m, 2H), 2.00-2.04 (m, 2H), 2.90 (m, 1H), 3.13 (t, J=6.4 Hz,2H), 4.86 (br, 1H), 5.11 (s, 2H), 5.76 (br, 2H), 7.00 (d J=5.2 Hz, 1H),7.22 (d J=5.2 Hz, 1H), 7.31-7.37 (m, 5H). MS (ES+): m/z 5.7.36 [MH+].

Benzyl4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-1-carboxylate

A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride(2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) inDCM (27.0 mL) was treated with andN-(3-dimethylaminopropyl)-Al-ethylcarbodiimide hydrochloride (3.2 g,0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol).The mixture was stirred at rt overnight then diluted with DCM (30 mL),washed with sat. NaHCO₃ (20 mL) and brine (20 mL), then dried overNa₂SO₄ and concentrated in vacuo. The crude material thus obtained waschromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding3.38 g of the title compound. ¹H NMR (400 MHz, CDCl₃): δ 1.68-1.78 (m,2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m,2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m,5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z389.17 [MH+].

Benzyl 4(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

To a suspension of benzyl4-{[(3-chloropyrazin-2-yl)methyl]carbamoyl}piperidine-4-carboxylate(0.100 g, 0.220 mmol) in EtOAc (0.9 mL) and DMF (0.068 mL) at 0° C. wasslowly added POCl₃ (0.082 mL, 0.88 mmol). After stirring at rt for anhour the mixture was cooled to 0° C. then treated with solid NaHCO₃. Themixture was stirred for 20 min at rt, diluted with water and extractedwith EtOAc (3×20 mL). The combined extracts were washed with water (2×30mL) and brine (30 mL), then dried over Na₂SO₄, and concentrated in vacuoto yield 2.07 g of desired product. ¹H NMR (400 MHz CDCl₃): δ 1.98-2.04(m, 4H), 3.03-3.20 (m, 3H), 4.30-4.33 (m, 2H), 5.16 (s, 2H), 7.33 (d,J=5.2 Hz, 1H), 7.35-7.38 (m, 5H), 7.26 (d, J=4.4 Hz, 1H), 7.79 (s, 1H).MS (ES+): m/z 371.22 [MH+].

Benzyl4(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

To a solution of benzyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.31 g,0.00354 mol) in DMF (0.6 mL) was added NIS (1.6 g, 0.0071 mol). Thereaction mixture was left to stir at 55° C. for 20 h. then the mixturewas diluted with EtOAc (20 mL), washed with water (2×40 mL) and brine,then dried over Na₂SO₄ and concentrated in vacuo. The crude reactionmixture was chromatographed over silica gel eluting withhexane→hexane:EtOAc 1:1 yielding 1.63 g of desired product. ¹H NMR (400MHz, CDCl₃): δ 1.95-2.04 (m, 4H), 3.02-3.15 (m, 3H), 4.29-4.32 (m, 2H),5.15 (s, 2H), 7.32 (d, S=5.2 Hz, 1H), 7.34-7.37 (m, 5H), 7.66 (d, J=5.2Hz, 1H). MS (ES+): m/z 497.03 [MH+].

Benzyl4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

A mixture of benzyl4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate(0.500 g, 0.00101 mol) in IPA (20 mL) was cooled to at −78° C. andtreated with a stream of ammonia gas over 3 minutes. The resultingsolution was heated at 110° C. in a Parr vessel prior to concentrationin vacuo, suspension in DCM and filtration through a bed of Celite. Thefiltrate was concentrated in vacuo to afford 0.504 g of desired product¹H NMR (400 Adz, CDCl₃): δ 1.88-2.02 (m, 2H), 2.99-3.10 (m, 3H),4.24-4.41 (m, 2H), 5.15 s, 2H), 6.03 (br, 2H), 7.03 (d, J=4.8 Hz, 1H),7.24 (d, J=5.2 Hz, 1H), 7.31-7.40 (m, 5H). MS (ES+): m/z 479.33 [MH+].

1-(2-Trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridine

To a suspension of sodium hydride (934 mg, 0.0358 mol) in DMF (57 mL)was added dropwise under N₂, a solution of I H-pyrrolo[2,3-b]pyridine(3.00 g, 0.0254 mol) in DMF (20 mL). The mixture was stirred at r.t. for45 min. then cooled to 0° C. and treated dropwise with[2-(trimethylsilyl)ethoxy]methyl chloride (6.32 mL, 0.0357 mol). Themixture was stirred at rt for 12 h. then poured into water (10 mL),stirred for 30 min. and extracted with Et2O (4×10 mL). The combinedextracts were washed with brine (20 mL), dried over sodium sulfate, andconcentrated in vacuo to give the crude product which waschromatographed over silica gel eluting with hexane 1:9 Et₂O:hexane toafford 6 g desired product.

N-(2-Trimethylsilyl-1-ethoxymethyl)-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (500 mg,0.0020129 mol) in THF (5 mL) at −10° C. was added a 2.0 M of n-BuLi incyclohexane (1.2 mL). After 10 min at −10° C., the mixture was cooled to−20° C. and tributyltin chloride (0.65 mL, 0.0024 mol) was added. Themixture was stirred at rt for 1 h, the poured into a 5% aqueous ammoniumchloride (20 mL), extracted with EtOAc (3×20 mL) and the combinedextracts dried over anhydrous MgSO₄ and concentrated in vacuo. Thematerial thus obtained was chromatographed over silica gel eluting with1:9 EtOAc:hexane to afford 0.7 g of the title compound. ¹H NMR (400 MHzDMSO-d6) δ 0.01 (s, 9H), 0.10 (s, 2H), 0.92-0.94 (m, 9M, 1.14-1.27 (m,6H), 1.37-1.46 (m, 6H), 1.60-1.72 (m, 6H), 3.48-3.52 (m, 2H), 5.71 (s,2H), 6.74 (s, 1H), 7.16-7.19 (m, 1H), 8.02 (dd, J=1.6, 7.6 Hz, 1H) and8.31 (dd, J=1.6, 4.4 Hz, 1H).

3-cyclobutyl-1-[1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]imidazo[1,5-a]pyrazin-8-amine

A mixture ofN-(2-trimethylsilyl-1-ethoxymethyl)-2-(tributylstannyl)-1H-pyrrolo[2,3-b]pyridine(110 mg, 0.20 mmol), 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine(50 mg, 0.1592 mmol) and bis(triphenylphosphine)palladium(II) chloride(10 mg, 0.02 mmol) in ethanol (2 mL) was heated at reflux for 48 h. Themixture was then cooled to rt, filtered through a pad of Celite andconcentrated in vacuo. The residue thus obtained was chromatographedover silica gel eluting with hex:EtOAc to afford 17.2 mg of the titlecompound. ¹H NMR (400 MHz CDCl₃) δ 0.22 (s, 9H), 0.70 (t, 2H), 1.87-2.19(m, 2H), 2.49-2.64 (m, 4H), 3.37 (t, 2H), 3.81-3.86 (m, 1H), 5.51 (bs,2H), 6.07 (s, 2H), 6.67 (s, 1H), 7.10-7.16 (m, 3H), 7.93 (dd, J=1.6, 8.0Hz, 1H) and 8.41 (dd, J=1.6, 4.8 Hz, 1H). MS (ES+): m/z: 435.21 [MH+].

4-Bromo-2-nitro-N-phenylamine

A mixture of 1-bromo-4-fluoro-3-nitrobenzene (2270 mg, 10.01 mol),aniline (3 ml) and DMF (20 ml) was heated at 100° C. under an atmosphereof Nitrogen for 7 h. The mixture was then concentrated in vacuo, and theresidue triturated with heptane (30 ml) to give the desired product. 1HNMR (400 MHz, CDCl₃) δ=7.11 (d, 1H, J=9.2 Hz), 7.25-7.29 (m, 3H),7.40-7.45 (m, 3H), 8.35 (d, 1H J=2.4 Hz) and 9.45 firs, 1H).

4-Bromo-N-methyl-2-nitroaniline

Prepared according to a procedure analogous to that described for4-bromo-2-nitro-N-phenylaniline. ¹H NMR (400 MHz, CDCl₃): δ=3.02 (d, 3H,J=5.2 Hz), 6.76 (d, 1H, J=9.6 Hz), 7.51-7.54 (m, 1H), 8.02 (brs, 1H) and8.32 (d, 1H, J=2.8 Hz). MS (ES+): m/z 231.05 and 233.08[MH+].

4-Bromo-N-ethyl-2-nitroaniline

Prepared according to a procedure analogous to that described for4-bromo-2-nitro-N-phenylaniline. ¹H NMR (400 MHz, CDCl3) δ=1.37 (t, 3H,J=7.2 Hz), 3.31-3.37 (m, 2H), 6.76 (d, 1H, J=8.8 Hz), 7.48-7.51 (m, 1H,7.95 (brs, 1H) and 8.31 (d, 1H, J=2.4 Hz). MS (ES+): m/z 245.07 and247.11 [MH+].

N-Benzyl-4-bromo-2-nitroaniline

Prepared according to a procedure analogous to that described for4-bromo-2-nitro-N-phenylaniline. ¹H NMR (4006 MHz, CDCl₃) δ=4.54 (d, 2H,J=5.6 Hz), 6.72 (d, 1H, J=9.2 Hz), 7.30-7.40 (m, 5H), 7.44 (ddd, 1H,J=0.4 & 2.4 & 9.2 Hz), 8.34 (d, 1H, J=2.4 Hz) and 8.41 (brs, 1H). MS(ES+): m/z 245.07 and 247.11 [MH+].

4-Bromo-N¹-phenylbenzene-1,2-diamine

Prepared according to a procedure analogous to that described for4-bromo-2-nitro-N-phenylaniline. ¹H NMR (400 MHz, DMSO-d₆)=3.80 (brs,2H), 5.07 (br, s, 1H), 6.70-6.75 (m, 2H), 6.82-6.86 (m, 2H), 6.93 (d,1H, J=2.4 Hz), 6.97 (d, 1H, J=8.0 Hz) and 7.17-7.24 (m, 2H). MS (ES+):m/z 263.17 and 265.20 [MH+].

4-Bromo-N¹-methylbenzene-1,2-diamine

A suspension of 4-bromo-N-methyl-2-nitroaniline (5328 mg, 22.04 mmol) inEtOH (100 ml) was treated with SnCl₂.2H₂O (25.61 g, 110.2 mmol) and theresulting mixture heated at 70° C. under an atmosphere of Nitrogen for 5h. The reaction mixture was then cooled to rt and treated with ice-water(50 ml) followed by aqueous NaOH (4 N) until pH>8. This basic mixturewas then extracted with EtOAc (3×150 ml) and the combined extractswashed with brine (3×100 ml), dried over MgSO₄ and concentrated in vacuoto afford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm=2.68 (s,3H), 4.74 (brs, 3H), 6.27 (d, 1H, J=8.4 Hz), 6.61 (dd, 1H, J=2.0 & 8.4Hz) and 6.66 (d, 1H, J=2.0 Hz). MS (ES+): m/z 201.10 and 203.12 [MH+].

4-Bromo-N′-ethylbenzene-1,2-diamine

Prepared according to a procedure analogous to that described for4-bromo-N′-methylbenzene-1,2-diamine. ¹H NMR (400 Mhz, DMSO-d₆) δppm=1.19 (t, 3H, J=6.8 Hz), 3.01 (quartet, 2H, J=6.8 Hz), 4.46 (brs,1H), 4.81 (brs, 2H), 6.30 (d, 1H, J=8.4 Hz), 6.58 (dd, 1H, J=2.4 & 8.4Hz) and 6.66 (d, 1H, J=2.0 Hz). MS (ES+): m/z 215.07 and 217.16 [MH+].

N¹—Benzyl-4-bromobenzene-1,2-diamine

Prepared according to a procedure analogous to that described for4-bromo-N¹-methylbenzene-1,2-diamine. ¹H NMR (400 MHz, DMSO-d₆) δppm=3.39 (brs, 2H), 3.61 (brs, 1 H), 4.28 (s, 2H, 6.51 (d, 1H, J=8.4Hz), 6.85-6.89 (m, 2H) and 7.27-7.38 (m, 5H). MS (ES+): m/z 277.20 and279.20 [MH+].

1-Benzyl-5-bromo-2-phenyl-1H-benzimidazole

p-TsOH.H₂O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution ofN′-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethylorthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture wasstirred at rt under an atmosphere of Nitrogen for 40 h. The reactionmixture was then concentrated in vacuo to give a yellow solid which wastriturated with 40% MeOH/water (375 mL), filtered, washed with saturatedNaHCO₃ (20 ml)+H₂O (80 ml) twice and 40% MeOH/H₂O (2×50 ml), and driedto give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm=5.44 (s, 2H,7.05-7.08 (m, 3H), 7.30-7.36 (m, 4H), 7.44-7.50 (m, 3H), 7.66-7.68 (m,2H) and 7.99 (dd, 1H, J=0.4 & 1.6 Hz). MS (ES+): m/z 363.20 and 365.26[MH+].

5-Bromo-1-methyl-2-phenyl-1H-benzimidazole

Prepared according to a procedure analogous to that described for1-benzyl-5-bromo-2-phenyl-1H-benzimidazole. ¹H NMR (400 z, CDCl₃) δppm=3.86 (s, 3H), 7.26-7.29 (m, 1H), 7.42 (dd, 1H, J=2.0 & 8.4 Hz),7.53-7.56 (m, 3H), 7.74-7.76 (m, 2H) and 7.95 (dd, 1H, J=0.4 & 1.6 Hz).MS (ES+): m/z 287.18 and 289.14 [M+].

5-Bromo-1-ethyl-2-phenyl-1H-benzimidazole

Prepared according to a procedure analogous to that described for1-benzyl-5-bromo-2-phenyl-1H-benzimidazole ¹H NMR (400 MHz, CDCl₃) δppm=1.46 (t, 3H, J=7.2 Hz), 4.27 (quartet, 2H, J=7.2 Hz), 7.27 (m, 1H),7.30 (dd, 1H, J=0.4 & 8.8 Hz), 7.42 (dd, 1H, J=1.6 & 8.8 Hz), 7.53-7.55(m, 3H), 7.70-7.72 (m, 2H) and 7.96 (dd, 1H, J=0.4 & 1.6 Hz). MS (ES+):m/z 301.18 and 303.11 [MH+].

5-Bromo-1,2-diphenyl-1H-benzimidazole

Prepared according to a procedure analogous to that described for1-benzyl-5-bromo-2-phenyl-1H-benzimidazole. ¹H NMR (400 MHz, CDCl₃):δ=7.11 (dd, 1H, J=0.4 & 8.4 Hz), 7.27-7.39 (m, 6H), 7.48-7.56 (m, 5H)and 8.01 (dd, 1H, J=0.4 & 1.6 Hz). MS (ES+): m/z 349.20 and 351.22[MH+].

1-Methyl-2-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole

A mixture of 5-bromo-1-methyl-2-phenyl-1H-benzimidazole (616 mg, 2.14mmol), [1,1′—Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (52.6 mg, 0.0644 mmol),bis(pinacolato)diboron (667 mg, 2.57 mmol),1,1′-bis(diphenylphosphino)ferrocene (36.8 mg, 0.0644 mmol) and AcOK(638 mg, 6.44 mmol) in 1,4-dioxane (10 ml) was purged with N₂ for 5 min,and was then heated at 100° C. under an atmosphere of Nitrogen for 16 h.The mixture was then treated with saturated NH₄Cl (20 ml), extractedwith EtOAc (3×20 ml) and the combined extracts washed with brine (3×20ml), dried over MgSO₄ and concentrated in vacuo to afford crude productwhich was purified by chromatography over silica gel eluting with 30%(250 ml) and 40% (250 ml) EtOAc/Heptane to give a white solid that wastriturated with 50% EtOAc/Heptane (10 ml) to yield the title compound.¹H NMR (400 MHz, CDCl₃) δ ppm=1.38 (s, 12H), 3.86 (s, 3H), 7.39 (dd, 1H,J=1.2 & 8.0 Hz), 7.50-7.55 (m, 3H), 7.76-7.79 (m, 3H) and 8.29 (d, 1H,J=0.8 Hz). MS (ES+): m/z 335.29 (100) [MH+].

1-Ethyl-2-phenyl-5(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole

Prepared according to a procedure analogous to that described for1-Methyl-2-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole.¹H NMR (400 MHz, CDCl₃) δ ppm=1.38 (s, 12H), 1.45 (t, 3H, J=7.2 Hz),4.28 (quartet, 2H, J=7.2 Hz), 7.42 (dd, 1H, J=0.8 & 8.0 Hz), 7.51-7.54(m, 3H), 7.71-7.74 (m, 2M, 7.77 (dd, 1H, J=0.8 & 8.0 Hz) and 8.31 (s,1H). MS (ES+): m/z 349.33 [MH+].

1-Benzyl-2-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole

Prepared according to a procedure analogous to that described for1-Methyl-2-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole.¹H NMR (400 z, CDCl₃) δ ppm=1.36 (s, 12H), 5.45 (s, 2H), 7.05-7.08 (m,1H), 7.21 (dd, 1H, J=0.8 & 8.0 Hz), 7.26-7.31 (m, 3H), 7.44-7.48 (m,3H), 7.66-7.71 (m, 3H) and 8.36 (m, 1H). MS (ES+): m/z 411.42 [MH+].

1,2-Diphenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole

Prepared according to a procedure analogous to that described for1-Methyl-2-phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole.¹H NMR (400 MHz, CDCl₃) δ ppm=1.38 (s, 12H), 7.22 (dd, 1H, J=0.8 & 8.0Hz), 7.29-7.35 (m, 5H), 7.47-7.50 (m, 3H), 7.55-7.57 (m, 2H) and 7.71(dd, 1H, J=0.8 & 8.0 Hz), 8.38 (m, 1H). MS (ES+): m/z 397.43 [MH+].

7-Chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-1H-indole

A flask containing Ir(Ome)₂(COD)₂ [Inorganic Syntheses (1985), 23, 126](850 mg, 0.0013 mol), 4,4′-di-tert-butyl-[2,2′]bipyridinyl (686 mg,0.00256 mol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (15.2 g,0.0600 mol) was evacuated and refilled with Ar (3×), then charged withanhydrous DIE (400 mL, 3 mol) and a solution of 7-chloro-1H-indole(0.086 mol) in DE (10 mL). The resulting mixture was stirred under Arfor 16 h then concentrated and chromatographed over silica gel elutingwith 10% EtOAc/Heptane to afford the desired product as a waxy solid ina 96% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.39 (s, 12H), 7.04 (t,J=7.71 Hz, I H), 7.15 (d, J=2.27 Hz, 1H), 7.21-7.30 (m, 1H), 7.58 (d,J=8.08 Hz, 1H) and 8.72 (br. s., 1H).

4-Methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 4-methoxy-1H-indole.

7-Bromo-4-methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-bromo-4-methoxy-1H-indole.

7-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-methyl-1H-indole.

7-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-fluoro-1H-indole.

4-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 4-methyl-1H-indole.

4-Methoxy-1-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 4-methoxy-1-methyl-1H-indole.

7-Ethyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-II-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-ethyl-1H-indole.

4,7-Dimethoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 4,7-dimethoxy-1H-indole.

2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-4-yl acetate

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 1H-indol-4-yl acetate.

2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-4-carboxylicAcid, Methyl Ester

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 1H-indole-4-carboxylic acid, methyl ester.

7-Methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-methoxy-benzofuran.

4,4,5,5-Tetramethyl-2-(3-methyl-benzo[b]thiophen-2-yl)[1,3,2]dioxaborolane

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 3-methyl-benzo[b]thiophene.

3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 3-methyl-benzofuran.

7-Bromo-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-bromo-1H-indole.

3-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 3-methyl-1H-indole.

7-Methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-methyl-benzofuran.

7-Methoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-methoxy-1H-indole.

7-Ethoxy-1H-indole

To a stirred solution of 1H-indol-7-ol (500 mg, 3.75 mmol) in acetone(10 mL) at r.t. was added potassium carbonate (3.11 g, 22.5 mmol),followed by iodoethane (0.45 mL, 5.63 mol). The mixture was stirred atr.t for 16 h then solvent removed under reduced pressure. The crudeproduct thus obtained was purified by chromatography over silica gel toafford 7-ethoxy-1H-indole: ¹H NMR (400 MHz, MeOD) δ ppm 1.51 (t, J=6.95Hz, 3H), 4.22 (q, J=6.91 Hz, 2H), 6.42 (d, J=3.03 Hz, 1H), 6.63 (d,J=7.58 Hz, 1H), 6.92 (t, J=7.83 Hz, 1H), 7.04-7.23 (m, 2H); MS (ES+):m/z 162.20 (MH+).

7-Ethoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-ethoxy-1H-indole.

7-Isopropoxy-1H-indole

Made according to the procedure described for 7-ethoxy-1H-indole using2-iodopropane.

7-Isopropoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-isopropoxy-1H-indole.

7-Trifluoromethyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

To a stirred mixture of 7-trifluoromethyl-1H-indole-2,3-dione (116 mg)in THF (5.00 mL) was added boron trifluoride etherate (0.205 mL, 1.62mmol) followed by sodium borohydride (71.4 mg, 1.88 mmol). The resultingmixture was stirred at −20° C. for 2 hrs, then water (1 mL) was addedand the mixture was stirred at 0° C. for 10 min. The solution wasacidified to pH=1 with 2N HCl, warmed to r.t. and stirred at r.t. for 20min prior to extraction with EtOAc. The extracts were dried overmagnesium sulphate, concentrated in vacuo and the residue purified bychromatography over silica gel eluting with hexane to give7-trifluoromethyl-1H-indole. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.63-6.68(1H, m), 7.20 (1H, t, J=7.71 Hz), 7.30-7.35 (1H, m), 7.47 (1H, d, J=7.33Hz), 7.83 (1H, d, J=8.08 Hz), and 8.56 (1H, br. s.).

7-Trifluoromethyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-trifluoromethyl-1H-indole.

Ethyl N-[2(trifluoromethoxy)phenyl]carbamate

Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and thereaction mixture stirred at room temperature overnight. The reactionmixture was then washed with ether, acidified (pH 3) and the productextracted into EtOAc (3×40 mL). The combined extracts were washed withwater (40 mL) and brine (40 mL), dried over Na2SO4 and the solventremoved in vacuo to give the desired product in a 84% yield. ¹H NMR (400MHz, CDCl₃): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br,1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+):m/z 250.12 [MH+].

Ethyl N-[2-iodo-6-(trifluoromethoxy)phenyl]carbamate

A 1.4 M solution of sec-butyllithium in cyclohexane (3.0 mL) was addeddrop-wise to a solution of ethyl N-[2-(trifluoromethoxy)phenyl]carbamate(0.5000 g, 0.002006 mol) in THF (9 mL) at −70° C. After stirring for 1hour a solution of iodine (0.51 g, 0.002 mol) in THF (1.0 mL) was addeddrop-wise at −70° C. Stirring was continued for another 1 hour then themixture was quenched with saturated ammonium chloride solution. Water(50 mL) was added and the mixture extracted with diethyl ether (3×40mL). The combined organic phases was washed with 40% sodiummeta-bisulfite solution, water and brine, then dried over Na2SO4 and thesolvent removed in vacuo to give the desired product in a 73% yield. ¹HNMR (400 MHz, CDCl₃): δ 1.29-1.36 (m, 3H), 4.21-4.28 (m, 2H), 6.21 (br,1H), 7.05 (t, J=8.0 Hz, 1H), 7.30 (m, 1H) and 7.80 (dd, J=6.8, 1.2 Hz,1H). MS (ES+): m/z 375.78 [MH+].

Ethyl [2-trifluoromethoxy-6-(trimethylsilanylethynylphenyl)]carbamate

A mixture of Pd(PPh3)2Cl2 (83 mg, 0.00012 mol) and copper (I) iodide (23mg, 0.00012 mol) in triethylamine (44 mL, 0.32 mol) was heated at 40° C.for 20 min then cooled tort and ethyl[2-iodo-6-(trifluoromethoxy)phenyl]carbamate (4.50 g, 0.0120 mol) wasadded in one portion. The mixture was stirred at room temperature for 30min, then (trimethylsilyl)acetylene (1.6 mL, 0.011 mol) was added andthe mixture stirred for a further 2 hours. The solvent was removed invacuo and the residue was partitioned between water and diethyl ether(60 mL of each). The organic was washed with 1N HCl and brine, thendried over Na2SO4 then the solvent removed in vacuo. The reaction waschromatographed over silica gel eluting with 20% EtOAc/hexane to affordthe desired product in 80% yield. MS (ES+): m/z 345.99 [MH+].

7-Trifluoromethoxy-1H-indole

Sodium ethoxide (0.65 mL, 0.0017 mol, 2.6M) was added to a solution ofethyl [2-trifluoromethoxy-6-(trimethylsilanylethynylphenyl)]carbamate inEtOH (5.0 mL) and the mixture stirred at 72° C. for 14 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between diethyl ether and water (30 mL of each). The etherphase was washed with brine and dried over Na₂SO₄ yielding the desiredcompound in 59% yield. ¹H NMR (400 Adz, CDCl₃): δ 6.60-6.61 (m, 1H),7.07-7.09 (m, 2H), 7.25 (d, J=5.6 Hz, 1H), 7.55-7.57 (m, 1H) and 8.42(br, 1H). MS (ES+): m/z 202.18 [MH+].

7-Trifluoromethoxy-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-trifluoromethoxy-1H-indole.

7-Phenyl-1H-indole

To a suspension of 7-bromo-1H-indole (196 mg, 0.00100 mol) in1,4-dioxane (4 mL) and water (1 mL) was added phenylboronic acid (146mg, 0.00120 mol), potassium carbonate (414 mg, 0.00300 mol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (82 mg, 0.00010 mol). The flask was evacuatedand refilled with nitrogen, three times then the mixture was heated at100° C. overnight. The mixture was diluted with EtOAc (30 mL), washedwith sat. aq. NaHCO₃ (10 mL) and brine (10 mL), then dried overanhydrous sodium sulfate and the solvent removed in vacuo. The crudematerial was purified by chromatography over silica gel eluting withhexane/EtOAc to give the title compound (180 mg, 93% yield). ¹H NMR(CDCl₃, 400 MHz): δ 6.64 (dd, J=3.0, 2.0 Hz, 1H), 7.18-7.26 (m, 3H),7.41 (t, J=7.5 Hz, 1H), 7.48-7.57 (m, 2H), 7.61-7.70 (m, 3H) and 8.43(br s, 1H) ppm. LC-MS (ES+): 194 [MH⁺].

7-Phenyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

Prepared according to a procedure analogous to that described for7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing 7-phenyl-1H-indole.

7-Cyclopropyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-indole

Prepared according to the procedures described above for7-phenyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indoleusing cyclopropylboronic acid in place of phenylboronic acid. ¹H NMR(CDCl₃, 400 MHz): δ 0.75-0.82 (m, 2H), 0.95-1.04 (m, 2H), 2.08 (m, 1H),6.59 (dd, J=3.0, 2.0 Hz, 1H), 6.96 (d, J=7.1 Hz, 1H), 7.06 (t, J=7.6 Hz,1H), 7.25 (m, 1H), 7.52 (d, J=7.8 Hz, 1H) and 8.39 (br s, 1H) ppm. LC-MS(ES, Pos.): 158 [MH⁺].

6-Bromo-7-fluoro-1H-indole

To a solution of 1-bromo-2-fluoro-3-nitrobenzene (2.5 g, 11.3 mmol) inTHF (25 mL) at −50° C. was added vinyl magnesium bromide (34 mL, 34mmol) and the mixture was stirred at 40° C. for 1 h. The reaction wasquenched with saturated ammonium chloride solution and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure to yielda gun, which was purified by column chromatography over silica geleluting with EtOAc/hexane to afford pure 6-bromo-7-fluoro-1H-indole. ¹HNMR (400 MHz, CDCl₃) δ=6.53-6.62 (m, 1H), 7.16-7.25 (m, 2H), 7.29 (d,J=8.34 Hz, 1H) and 8.36 (br. s., 1H); MS (ES+): m/z 214.08 [MH+].

6-Bromo-7-fluoro-1-methyl-1H-indole

To a solution of 6-bromo-7-fluoro-1H-indole (470 mg, 2.19 mmol) in THF(7 mL) at −10° C. was added sodium hydride (175 mg, 4.39 mmol, 60%dispersion) and the mixture was stirred at 0° C. for 30 min. Methyliodide was added at 0° C. and the reaction was allowed to warm to at 10°C. and stirred for 2 h. The reaction was quenched with saturatedammonium chloride and extracted with DCM. The DCM extract was washedwith brine, dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was purified by columnchromatography over silica gel eluting with EtOAc/hexane to afford6-bromo-7-fluoro-1-methyl-1H-indole. ¹H NMR (400 MHz, CDCl₃) δ=3.95 (d,J=2.00 Hz, 1H), 6.42 (t, J=2.78 Hz, 1H), 6.94 (d, J=3.03 Hz, 1H),7.09-7.15 (m, 1H) and 7.20 (d, J=8.34 Hz, 1H); MS (ES+): m/z 228.04[MH+].

7-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole

To a mixture of 6-bromo-7-fluoro-1-methyl-1H-indole (420 mg, 1.84 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (514 mg, 2.02mmol), potassium acetate (542 mg 5.52 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1 complex, 150 mg, 0.184 mmol) and1,1′-bis(diphenylphosphino)ferrocene (102 mg, 0.184 mmol) was addeddioxane (10 mL) and the mixture was degassed by bubbling through withnitrogen for 3 min. The reaction mixture was heated at 100° C. overnightthen the dioxane was removed under reduced pressure and the residue wasdissolved in DCM and filtered to remove inorganics. The filtrate wasconcentrated and the crude product was purified by column chromatographyover silica gel eluting with EtOAc/hexane to afford pure7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole.¹H NMR (400 MHz, CDCl₃) δ=1.41 (s, 12H), 4.02 (d, J=2.02 Hz, 3H), 6.46(t, J=2.65 Hz, 1H), 7.03 (d, J=3.03 Hz, 1H) and 7.28-7.47 (m, 2H); MS(ES+): m/z 276.03 [MH+].

7-Trifluoromethyl-benzo[b]thiophene

To a stirred solution of 2-(trifluoromethyl)benzenethiol (5.000 g, 0.028mol) in acetone (50 mL) was added 2-bromo-1,1-diethoxyethane (6.08 g,0.030 mol) and potassium carbonate (7.757 g, 0.056 mol). The resultingmixture was then stirred at 45° C. for 2 hours prior to removal of thesolvent in vacuo and suspension of the residue in EtOAc. The inorganicsalts were filtered off and the organic phase was concentrated to givecrude product, which was used in next step without further purification.This residue was dissolved in toluene (50 mL), and to this solution wasadded PPA (10 g) and the resulting mixture stirred at 95-100° C. for 2hours. The mixture was allowed to cool to r was poured into ice-water,then extracted with EtOAc (3×50 ml). The combined extracts were washedwith aqueous sodium bicarbonate followed by brine, then dried overanhydrous sodium sulfate and evaporated under reduced pressure to yieldan oil. This was purified by column chromatography over silica geleluting with hexane to give 7-trifluoromethyl-benzo[b]thiophene. ¹H NMR(400 MHz, MeOD) δ ppm 7.49-7.57 (m, 2H), 7.70 (d, J=7.33 Hz, 1H), 7.74(d, J=5.56 LIZ, 1H) and 8.10 (d, J=8.08 Hz, 1H).

7-Trifluoromethylbenzo[b]thiophene-2-boronic Acid

To a solution of 7-trifluoromethyl-benzo[b]thiophene (0.52 g, 0.0026mol) in THF (30 mL) at −78° C. was added 2.5 M of n-BuLi in hexane (1.4mL). The reaction was then slowly warmed up to −30° C. over 30 min. andstirred at this temperature for 10 min prior to recooling to −78° C. andtreatment with triisopropyl borate (0.7255 g, 0.0038 mol). The reactionwas then slowly warmed up to 0° C. then was quenched with saturatedammonium chloride and the solvent removed in vacuo. To the residue wasadded aqueous sodium hydroxide (10 mL, 2N solution) followed by water(30 mL) then this mixture was extracted with DCM. The aqueous solutionwas acidified using dilute sulfuric acid (2N solution), filtered and theresidue dried in vacuo to yield7-trifluoromethylbenzo[b]thiophen-2-boronic acid. ¹H NMR (400 MHz, MeOD)δ ppm 7.55 (1H, t, J=7.45 Hz), 7.75 (1H, d, J=7.07 Hz), 8.02 (1H, s) and8.17 (1H, d, J=#7.83 Hz).

N-Methylindole-6-boronic Acid

A mixture of indole-6-boronic acid (0.100 g, 0.615 mol), sodium hydride(0.07 g, 20 mmol) and THF (5 mL, 60 mmol) was stirred at rt for 20 min.then methyl iodide (100 uL, 20 mmol) was added and the mixture wasallowed to stir at rt for 3 hours. The reaction was quenched with sat.NH₄Cl solution, washed with brine and dried over Na₂SO₄, then thesolvent was removed in vacuo. The crude product was purified bychromatography over silica gel eluting with 1:9 EtOAc/hexane and 1%MeOH, yielding the desired product. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.99(s, 3H), 6.58 (m, 1H). 7.23 (m, 1H), 7.81 (m, 1H), 8.08 (m, 1H) and 8.34(m, 1H). MS (ES+): m/z 176.15 [MH+].

4-Bromo-3-methyl-2-nitrophenol

To a solution of 3-methyl-2-nitrophenol (2.0 g, 13.06 mmol) in aceticacid (40 mL) was added bromine (0.70 mL, 13.71 mmol) and the mixture wasstirred at RT for 5 h. The reaction was poured in to ice water and theyellow precipitate formed was filtered and washed with water and driedin vacuo to yield 4-bromo-3-methyl-2-nitrophenol. ¹H NMR (400 MHz,CDCl₃) δ=2.61 (s, 3H), 2.62 (s, 5H), 6.92 (d, J=8.84 Hz, 1H), 7.66 (d,J=9.09 Hz, 1H) and 9.28 (s, 1H); MS (ES+): m/z 215.00 [M-17].

1-Bromomethoxy-2-methyl-3-nitrobenzene

To a solution of 4-bromo-3-methyl-2-nitrophenol (2.200 g, 9.48 mmol) inacetone (35 mL) was added potassium carbonate (3.276 g, 23.70 mmol) andmethyl iodide (1.47 mL, 23.70 mmol) and the mixture was heated to refluxfor 4 h. The reaction was cooled to rt, filtered and the filtrate wasevaporated under reduced pressure to afford the crude product.Purification of the crude product by column chromatography over silicagel eluting with EtOAc/hexane afforded pure1-bromo-4-methoxy-2-methyl-3-nitrobenzene as pale yellow solid. ¹H NMR(400 MHz, CDCl₃) δ=2.33 (s, 2H), 3.87 (s, 3H), 6.78 (d, J=8.84 Hz, 1H)and 7.58 (d, J=8.84 Hz, 1H); MS (ES+): m/z 247.26 [MH+].

1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine

To a solution of 1-bromo-4-methoxy-2-methyl-3-nitrobenzene (1.400 g,5.68 mmol) and 1,1-dimethoxy-N,N-dimethylethanamine (0.884 mL, 6.657mmol) in DMF (10.0 mL) was added pyrrolidine (0.555 mL, 6.656 mmol) andthe mixture was heated to at 110° C. for 4 h. The DMF was removed andthe residue was recrystallized from DCM:methanol (1:6) mixture to afford1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine.

4-Bromo-7-methoxy-1H-indole

To a solution of1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine (1.3 g, 3.97mmol) in THF (6 mL) and methanol (6 mL) was added Raney Ni (≈500 mg)followed by hydrazine (0.19 mL). (CAUTION: Exothermic reaction withvigorous gas evolution). Hydrazine (0.19 mL) was added again, two times,after 30 min and 1 h. The reaction was stirred at 45° C. for 2 h,filtered through a pad of celite. The filtrate was concentrated in vacuoand the residue purified by chromatography over silica gel eluting withEtOAc/hexane to afford pure 4-bromo-7-methoxy-1H-indole. H NMR (400 MHz,CDCl₃)=3.94 (s, 3H), 6.52 (d, J=8.08 Hz, 1H), 6.56 (dd, J=3.16, 2.40 Hz,1H), 7.17 (d, J=8.08 Hz, 1H), 7.22 (t, J=2.78 Hz, 1H) and 8.47 (br. s.,1H); MS (ES+): m/z 226.12 [MH+].

2-Phenyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-benzothiazole

A stirred solution of 5-bromo-2-phenylbenzothiazole (0.500 g, 0.00172mol), bis(pinacolato)diboron (0.508 g, 0.00200 mol),1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride (0.044 g,0.10 mmol), Pd(OAc)₂ (0.019 g, 0.086 mmol) and AcOK (0.423 g, 0.00431mol) in anhydrous THF (9.78 mL, 0.121 mol) was heated at 72° C. underArgon for 29 h. The mixture was filtered through a multi-layered pad ofanhydrous sodium sulfate, silica gel and celite and the filtrate wasconcentrated in vacuo and the solids triturated multiple times withhexanes to give the title compound. ¹H NMR (400 MHz, CHLOROFORM-d) δppm=1.39 (s, 12H), 7.49-7.56 (m, 3H), 7.83 (dd, J=8.08, 1.01 Hz, 1H,7.92 (d, J=7.33 Hz, 1H), 8.12-8.18 (m, 2H) and 8.60 (s, 1H); MS (ES+):m/z 337.91 [MH+].

4-(Methoxycarbonyl)-4-methylcyclohexanecarboxylic Acid

N,N-Diisopropylamine (1.18 mL, 8.35 mmol) was added dropwise to a 2Msolution of ^(n)butyllithium (4.18 mL, 8.4 mmol) at −78° C. undernitrogen. After 15 min at this temperature the solution was raised toand held at 0° C. for 15 min prior to re-cooling to −78° C. andtreatment with a solution of 4-(methoxycarbonyl)cyclohexanecarboxylicacid (0.62 g, 3.34 mmol) in THF (8 mL). After 30 min., iodomethane (0.31mL, 5 mmol) was added dropwise and the mixture was allowed to warm to rtover 2 hr. The mixture was cooled to at 0° C., quenched with 2 N HCl (10mL) then was extracted with EtOAc (2×10 mL), washed with brine (3×15mL), and dried over anhydrous magnesium sulfate. Concentration of thecombined organic extracts afforded a yellow solid. NMR(CDCl₃) consistentwith crude, desired product.

Methyltrans-4-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}cyclohexanecarboxylate

A solution of N-hydroxysuccinimide (6.18 g, 0.0537 mol) andtrans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (10.00 g, 0.05370mol) in THF (100.00 mL) was charged with (N,N′-dicyclohexylcarbodiimide(11.08 g, 0.0537 mol) in THF (16 mL). This reaction was stirred at rtfor an additional 16 h then stirred at 45° C. for 1 h. The reactionmixture was filtered while still warm through a flitted funnel. The cakewas washed with 3 more portions of THF and the filtrate was concentratedin vacuo and was crystallized from i-PrOH (300 mL) and filtered througha flitted funnel resulting in 11.8 g, (78% yield) of the title compoundas a white crystals. ¹H NMR (400 MHz, CDCl3) δ ppm 1.45-1.69 (m, 4H),2.07-2.16 (m, 2H), 2.18-2.28 (m, 2H), 2.29-2.39 (m, 1H), 2.59-2.71 (m,1H) 2.84 (br. s., 4H) and 3.68 (s, 3H); MS (ES+): m/z 284.09 [MH+].

Methyltrans-4-{[3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]carbamoyl}cyclohexanecarboxylate

A solution of 3-amino-6-(aminomethyl)-1,2,4-triazin-5(4H)-one [J.Heterocyclic Chem., (1984), 21 (3), 697] (2.00 g, 0.0113 mol) in H₂O(60.0 mL, 3.33 mol) was cooled to 0° C. and drop wise charged with 1.00M of NaHCO₃ in H₂O (22.5 mL) and allowed to warm to rt. This mixture wascharged with methyltrans-4-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}cyclohexanecarboxylate(3.8 g, 0.012 mol) in 1:1 THF/MeCN (40 mL). After 30 min a precipitatebegan to form in the reaction. This was allowed to stir at rt for anadditional 16 h and was filtered through a fritted funnel and washedwith H₂O (2×), diethyl ether (2×), and dried in vacuo resulting in thetitle compound 2.92 g, (84% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.24-1.55 (m, 4H), 1.83 (s, 2H), 1.98 (d, J=10.61Hz, 2H), 2.27 (s, 2H), 3.64 (s, 3H), 4.10 (d, J=5.81H 2H), 6.81 (br. s.,2H), 7.91 (t, J=5.56 Hz, 1H) and 11.98 (br. s., 1H); MS (ES+): m/z310.05 [MH+].

Methyltrans-4(2-amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate

A solution of methyltrans-4-{[(3-amino-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl]carbamoyl}cyclohexanecarboxylate(2.00 g, 0.00646 mol) in 1,2-dichloroethane (130 mL) was charged withPOCl₃ (4.2 mL, 0.045 mol) and heated to reflux for 3 h. The reactionmixture was concentrated in vacuo then partitioned between EtOAc andsat. NaHCO₃ and separated. The aqueous was re-extracted with EtOAc (3×)and the combined organic fractions were dried over Na₂SO₄, filtered, andconcentrated in vacuo resulting in 1.43 g, (76% yield) of the titlecompound as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.43 (q,J=11.79 Hz, 2H), 1.61 (q, J=12.55 Hz, 2H), 1.85-2.11 (m, 4H), 2.38 (t,J=11.87 Hz, 1H), 2.98 (t, J=11.75 Hz, 1H), 3.61 (s, 3H), 6.17 (br. s.,2H), 7.49 (s, 1H) and 10.90 (br. s., 1H); MS (ES+): m/z 292.25 [MH+].

Methyltrans-4-(2-amino-5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate

A solution of methyltrans-4-(2-amino-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate(0.200 g, 0.000686 mol) and N-iodosuccinimide (0.278 g, 0.00124 mol) inanhydrous DMF (4.0 mL) was stirred at rt for 48 h. The reaction wasconcentrated in vacuo then partitioned between H₂O and EtOAc. Theaqueous material was re-extracted with EtOAc (3×) and the combinedorganic fractions were washed with H₂O (2×), Na₂S₂O₃ (2×) and brine(1×). The aqueous was re-extracted with CHCl₃ and combined with theEtOAc fractions dried over Na₂SO₄, filtered and concentrated in vacuoresulting in 229 mg, (79.9% yield) of the title compound as a lightorange solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.65 (m, 4H),1.88-2.06 (m, 4H), 2.33-2.45 (m, 1H), 2.91-3.01 (m, 1H), 3.61 (s, 3H),6.17 (s, 2H) and 10.82 (br. s., 1H); MS (ES+): m/z 417.82 [MH+].

Methyltrans-4-(5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate

A solution of methyltrans-4-(2-amino-5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate(0.880 g, 0.00211 mol) in anhydrous THF (74 mid) and DMF (13.2 mL) wascharged with tert-butyl nitrite (1.2 mL, 0.010 mol) and stirred at rtfor 2 h. The reaction was concentrated in vacuo and was purified bychromatography over silica gel [eluting with 5% MeOH in CHCl₃] resultingin 570 mg, (67% yield) of the title compound as a pale orange solid. (¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.54 (m, 2H), 1.56-1.69 (m, 2H),1.92-2.06 (m, 4H), 2.36-2.46 (m, 1H), 3.02-3.14 (m, 1H), 3.61 (s, 3H),7.89 (d, J=3.28 Hz, 1H) and 11.79 (br. s., 1H); MS (ES+): m/z 402.86[MH+].

Methyltrans-4-(4-amino-5-iodoimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate

A solution of 1H-1,2,4-triazole (0.881 g, 0.0128 mol) in pyridine (3.00mL) was charged with POCl₃ (0.396 mL, 0.00425 mol) and stirred at rt for15 min. To this mixture was drop wise added methyltrans-4-(5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate(0.570 g, 0.00142 mol) in pyridine (6.00 mL) and stirred at rt for anadditional 2.45 h. The reaction was quenched with excess 2 M of NH₃ ini-PrOH (40.00 mL) at 0° C. and allowed to stir at rt for an additional 3h. The reaction was concentrated in vacuo and partitioned between EtOAcand sat. NaHCO₃ and separated. The aqueous was washed with EtOAc (3×)and the combined organic fractions were washed with brine (1×). Theaqueous was re-extracted with CHCl₃ (3×) and the organic was added tothe EtOAc fractions. The combined organic fractions were dried overNa₂SO₄, filtered and concentrated in vacuo. The crude brown/red solidwas purified by chromatography over silica gel [eluting with 5% MeOH inCHCl₃] resulting in 438 mg, (76% yield) of the title compound as a lightyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.54 (m, 2H),1.55-1.71 (m, 2H), 1.92-2.07 (m, 4H), 2.35-2.46 (m, 1H), 3.06-3.19 (m,1H), 3.61 (s, 3H), 6.77 (br. s., 1H) 7.86 (s, 1H) and 8.44 (br. s., 1H);MS (ES+): m/z 401.85 [MH+].

1-Chloro-2-[(2,2-diethoxyethyl)thio]benzene

To a solution of 2-chlorobenzenethiol (5.0 g, 34.5 mmol) in acetone (35mL) was added 2-bromo-1,1-diethoxyethane (7.15 g, 36.3 mmol) followed bypotassium carbonate (9.55 g, 69.1 mmol). The mixture was heated atreflux for 3 h. then cooled to rt, filtered and the filtrate evaporatedunder reduced pressure to yield the crude product. This material waspurified by chromatography over silica gel eluting with ethyl acetate inhexanes (0→2%) to afford pure1-chloro-2-(2,2-diethoxyethylsulfanyl)benzene (7.3, 80%). ¹H NMR (400MHz, CDCl₃) δ=1.20 (t J=7.07 Hz, 6H), 3.15 (d, J=5.56 Hz, 2H), 3.51-3.61(m, 2H), 3.63-3.74 (m, 2H), 4.69 (t, J=5.56 Hz, 1H), 7.12 (td, J=7.58,1.52 Hz, 1H), 7.20 (td, J=7.58, 1.52 Hz, 1H), 7.36 (dd J=−7.83, 1.52 Hz,1H), 7.39 (dd, J=8.08, 1.52 Hz, 1H); MS (ES+): m/z 187.17 [M-74].

7-Chlorobenzo[b]thiophene

To a solution of 1-chloro-2-(2,2-diethoxyethylsulfanyl)benzene (3.95 g,15.14 mmol) in toluene (40 mL) was added polyphosphoric acid (15 g,137.5 mmol). The mixture was heated at reflux for 4 h. then was pouredin to ice water, stirred for 30 min and extracted with toluene. Thecombined toluene extracts were washed with aqueous sodium bicarbonatefollowed by brine, dried over anhydrous sodium sulfate and evaporatedunder reduced pressure to yield the crude product. This material waspurified by chromatography over silica gel eluting with hexane to affordpure 7-chlorobenzo[b]thiophene (1.72 g, 67.5%). ¹H NMR (400 MHz, CDCl₃)δ=7.13-7.30 (m, 3H), 7.38 (d, J=5.31 Hz, 1H), 7.62 (dd, J=7.33, 1.52 Hz,1H); MS (ES+): m/z 169.06 [MH+].

7-Chlorobenzo[b]thiophene-2-boronic Acid

To a solution of 7-chlorobenzo[b]thiophene (1.0 g, 5.92 mmol) in THF (25mL) at −78° C. was added ^(n)butyllithium (7.41 mL 11.8 mmol, 1.6 Msolution). The reaction was allowed to warm to −30° C. then was cooledback to −78° C. and triisopropyl borate (2.23 g, 11.8 mmol) was added.The mixture was allowed to warm to 0° C., saturated ammonium chlorideadded and the organic phase separated off and concentrated in vacuo. Tothe residue was added aqueous sodium hydroxide (10 mL, 2N solution)followed by water (30 mL) and the mixture was washed with DCM. Theaqueous phase was acidified with 2N sulfuric acid, and the resultingprecipitate isolated by filtration and dried under vacuum to yield7-chlorobenzo[b]thiophene-2-boronic acid (1.21 g, 96%) as white solid.¹H NMR (400 MHz, CDCl₃) δ=7.41 (t, J=7.70 Hz 1H), 7.50 (d, J=7.70 Hz,1H), 7.91 (d, J=7.70 Hz, 1H), 8.03 (s, 1H), 8.63 (s, 2H); MS (ES+): m/z211.86 [M+].

7-(methylthio-1H-indole

To a solution of 7-bromo-1H-indole (3.0 g, 15.3 mmol) in THF (60 mL) at−78° C. was added ^(t)BuLi (1.7 M, 33.8 at, 57.4 mmol) and the mixturewas allowed to warm to 0° C. The reaction was re-cooled to −78° C. and asolution of dimethyl disulfide (2.0 mL, 22.9 mmol) was added and thereaction was allowed to warm to 0° C. The reaction was quenched withsaturated ammonium chloride and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand evaporated under reduced pressure to yield the crude product. Thismaterial was purified by chromatography over silica gel eluting withethyl acetate in hexanes (0-2%) to afford pure 7-(methylthio)-1H-indole(1.4 g, 55%). ¹H NMR (400 MHz CDCl₃) δ=2.50 (s, 3H), 6.58 (dd, J=3.03,2.02 Hz, 1H), 7.09 (t, J=7.58 Hz, 1H), 7.18-7.31 (m, 2H), 7.56 (d,J=7.83 Hz, 1H), 8.45 (br. s., 1H); MS (ES+): m/z 164.15 [MH+].

7-(Methylsulfonyl)-1H-indole

To a solution of 7-methylthio)-1H-indole (1.1 g, 6.7 mmol) in DCM (25ml) at 40° C. was added m-chloroperbenzoic acid (3.02 g, 13.4 mmol) andthe reaction was stirred at −40° C. for 30 min. The reaction mixture wasthen quenched with saturated sodium bicarbonate and extracted with DCM.The DCM extracts was washed with water, brine, dried over anhydroussodium sulfate and evaporated under reduced pressure to yield the crudeproduct. This material was purified by chromatography over silica geleluting with hexanes (0→10%) to afford pure 7-(methylsulfonyl)-1H-indole(987 mg, 75%). ¹H NMR (400 MEA CDCl₃) δ=3.12 (s, 1H), 6.66 (d, J=2.53Hz, 1H), 7.24 (t, J=7.71 Hz, 1H), 7.35 (d, J=1.77 Hz, 1H), 7.68 (d,J=7.07 Hz, 1H), 7.90 (d, J=7.83 Hz, 1H), 9.68 (br. s., 1H); MS (ES+):m/z 196.08 [MH+].

Methyl trans-4-cyanocyclohexanecarboxylate

Chlorosulfonyl isocyanate (1.0 mL, 0.012 mol) was added to a solution oftrans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 0.0107 mol)in DCM cooled to 0° C. The resulting solution was heated at reflux for15 minutes and then cooled 0° C. and treated dropwise with DM. Themixture was stirred at room temperature overnight then poured onto icewater and the organic phase separated and washed with a saturatedsolution of sodium bicarbonate. The solvent was removed in vacuo and thecrude material was taken up in ethyl acetate, washed with 1N aq. NaOH(10 mL) and the ethyl acetate removed in vacuo. The resulting crudeproduct was used in subsequent steps without further purification. ¹HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.70 (4H, m), 2.01-2.18 (4H, m),2.24-2.54 (2H, m) and 3.68 (3H, s).

Trans-4-cyanocyclohexanecarboxylic Acid

To a solution of methyl trans-4-cyanocyclohexanecarboxylate (996 mg,5.96 mmol) in THF (37 mL) was added a solution of 0.5 M lithiumhydroxide in water (20 mL). The mixture was stirred overnight then theTHF was removed in vacuo and the residual aqueous solution acidified topH 4. The resulting mixture was extracted with ether (2×30 mL), EtOAc(2×30 mL) and CHCl₃ (2×30 mL) then the combined extracts, dried overanhydrous sodium sulfate and concentrated in vacuo. This material wastaken to the next step without any purification. ¹H NMR (400 AdzCHLOROFORM-d) δ ppm 1.43-1.73 (4H, m), 2.05-2.22 (4H, m) and 2.36-2.59(2H, m).

2-[Trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]propan-2-ol

A solution of methyltrans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate (4.0g, 0.014 mol) in toluene (300 ml) and THF (70 mL) was cooled to 0° C.and treated with a 3.0 M solution of methylmagnesium bromide in ether(14 mL) maintaining the temperature at 0° C. The mixture was stirred atrt for 1.5 hours then cooled to 0° C. and an additional 3 eq of 3.0 M ofmethylmagnesium bromide in ether was added. The mixture was stirred atrt for 15 minutes then cooled to 0° C. and quenched with 1:1 NH₄Clsat.:H₂O (50 mL total volume). The organic layer was separated and theaqueous layer was extracted with EtOAc (3×30 mL). The combined organiclayers were dried over sodium sulfate and concentrated in vacuo and thecrude product thus obtained, chromatographed over silica gel elutingwith EtOAc to afford desired2-[trans-4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]propan-2-ol.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14-1.39 (m, 8H), 1.41-1.60 (m,1H), 1.77-1.98 (m, 2H), 2.01-2.20 (m, 4H), 2.78-3.06 (m, 1H), 7.35 (d,J=5.05 Hz, 1H), 7.64 (d, J=5-05 Hz, 1H) and 7.83 (s, 1H).

Example 1

3-Cyclobutyl-1-(1H-indol-5-yl)imidazo[1,5a]pyrazin-8-amine

A dry mixture of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine (30mg, 0.096 mmol), cesium carbonate (35 mg, 0.117 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (26 mg, 0.107mmol) was purged with Argon 3 times prior to the addition oftetrakistriphenylphosphino palladium (0) (6 mg, 0.005 mmol). The mixturewas purged twice more and then treated with a degassed mixture ofDME:water (5:1, 2 mL). The resulting solution was degassed twice moreand then heated at 80° C. overnight. The resulting reaction mixture wasconcentrated in vacuo, the residue dissolved in 1:1 MeCN:MeOH (1.5 mL)and purified by mass directed preparative HPLC to afford3-cyclobutyl-1-(1H-indol-5-yl)imidazo[1,5-a]pyrazin-8-amine H NMR (400MHz, DMSO-d₆) δ ppm 1.82-1.92 (1H, m) 1.95-2.08 (1H, m) 2.32-2.41 (4H,m) 3.82-3.93 (1H, m) 5.91 (2H, br. s.) 6.45 (1H, d, J=3.03 Hz) 6.90 (1H,d, J=5.05 Hz) 7.26 (1H, dd, J=8.34, 1.52 Hz) 7.34 (1H, d, J=5.05 Hz)7.35-7.39 (1H, m) 7.45 (1H, d, J=8.34 Hz) 7.64-7.68 (1H, m) 11.20 (1H,br. s.); MS (ES+): m/z 304.15 [MH+]. HPLC: t_(R) 6.18 min (XTerra C18 5uM, 4.6×15 mm, A: MeCN & B: 10 mmol NH₄OAc in 0.05% HOAc/aq., methodPolar15).

Example 2

3-Cyclobutyl-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared as described above for EXAMPLE 1 using1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid in place of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. The reactionconditions used effected significant cleavage of theN-(tert-butoxycarbamoyl) functionality. MS (ES+): m/z 304.10 [MH+].

Example 3

3-Cyclobutyl-1-(5-fluoro-If-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared as described above for EXAMPLE 1 using1-(tert-butoxycarbonyl)-5-fluoro-1H-indole-2-boronic acid in place of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. The reactionconditions used effected significant cleavage of theN-(tert-butoxycarbamoyl) functionality. MS (ES+): m/z 322.06 [MH+].

Example 4

1-(1-Benzothien-5-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

Prepared as described above for EXAMPLE 1 using2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane inplace of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS(ES+): m/z 321.10 [MH+].

Example 5

3-Cyclobutyl-1-(5-methyl-1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared as described above for EXAMPLE 1 using1-(tert-butoxycarbonyl)-5-methyl-1H-indole-2-boronic acid in place of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS (ES+): m/z318.05 [MH+].

Example 6

3-Cyclobutyl-1-(6-methyl-IM-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared as described above for EXAMPLE 1 using1-(tert-butoxycarbonyl)-6-methyl-1H-indole-2-boronic acid in place of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS (ES+): m/z318.05 [MH+].

Example 7

3Cyclobutyl-1-(1H-indol-6-yl)imidazo[1,5-a]pyrazin-8-amine

A mixture of 6-bromo-1H-indole (2 g, 10.00 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.00 g, 7.87mmol) and potassium acetate (3.0 g, 31.00 mmol) was degassed threetimes, treated with (1, 1′-bis(diphenylphosphino)ferrocene) palladiumdichloride (0.20 g, 0.28 mmol) and degassed twice more.1,2-dimethoxyethane (28 mL) was added and the mixture was heated at 75°C. overnight. The cooled reaction mixture was then diluted with water,extracted with EtOAc and the extracts washed with water and brine, thendried over magnesium sulphate, and concentrated in vacuo to afford abrown/black semi-solid. This was triturated with ether to afford a brownpowder, which was identified by LCMS to be desired indole-6-boronicacid, pinacol ester. ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.37 (s, 12H),6.54-6.58 (m, 1H), 7.26-7.28 (m, 1H), 7.55 (dd, J=7.83, 1.01 Hz, 1H),7.62-7.68 (m, 1H), 7.90 (s, 1H), 8.19 (br. s., 1H); MS (ES+): m/z 244.25[MH⁺]; HPLC: t_(R)=3.52 min (OpenLynx, polar_(—)5 min).

This material was used in place of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-1H-indole under theconditions described in EXAMPLE 1 to afford3-cyclobutyl-1-(1H-indol-4-yl)imidazo[1,5-a]pyrazin-8-amine. MS (ES+):m/z 304.15 [MH+].

Example 8

1-(1H-Benzimidazol-2-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

3-Cyclobutyl-1-iodoimidazo[1,5-a]pin-8-amine (500 mg, 2 mmol) andtetrakis(triphenylphosphine)palladium(0) (10 mg, 0.1 mmol) was degasseddry three times then treated with methanol (20 mL) andN,N-diisopropylethylamine (0.7 mL, 4.0 mmol) and the mixture heated at70° C. under an atmosphere of carbon monoxide, with intermittentbubbling of this gas under the surface of the reaction mixture. After 3d heating with extensive bubbling through of the solution with carbonmonoxide and some addition of fresh catalyst after day 2, TLC (10%MeOH/DCM indicated the reaction to be complete. The reaction mixture wasdiluted with water, extracted with DCM and the extracts washed withwater and brine, then dried over magnesium sulphate, and concentrated invacuo to afford an orange solid which was recrystallised fromacetonitrile to afford methyl8-amino-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxylate. ¹H NMR (400Adz, CHLOROFORM-d) δ ppm 1.97-2.06 (m, 1H), 2.10-2.26 (m, 1H), 2.43-2.54(m, 2H), 2.53-2.68 (m, 2H), 3.78 (dd, J=9.09, 8.08 Hz, 1H), 4.01 (s,3H), 7.08 (d, J=4.80 Hz, 1H), 7.22 (d, J=4.80 Hz, 1H), 7.38 (br. s.,1H), 7.69 (br. s., 1H).

A suspension of 1,2-phenylenediamine (60 mg, 0.6 mmol) in toluene (2.0mL) was treated with a 2M solution of trimethylaluminum in toluene (0.5mL) effecting the formation of a pink solution. After 5 min thissolution was treated with solid methyl8-amino-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxylate (30 mg, 0.1mmol) and the mixture heated at 120° C. for 30 min then stirred at rtovernight. The mixture was then partitioned between 2M NaOH (10 mL) &EtOAc (10 mL) and stirred for 15 min. The organic layer was separatedand the aqueous layer extracted further with EtOAc (3×10 mL). Thecombined organics were washed with brine, dried and concentrated invacuo to give ˜85% pure8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamidewhich was used without purification.

A solution of8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamide(40.0 mg, 0.124 mmol) in acetic acid (1.2 mL) was microwaved at 120° C.for 10 min (300 W). The resulting solution was purified mass directedpreparative HPLC to afford1-(1H-benzimidazol-2-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine. 1HNMR (400 MHz, DMSO-d6) δ ppm 1.92-2.05 (m, 1H) 2.07-2.21 (m, 1H)2.53-2.59 (m, 4H) 3.91-4.06 (m, 1H) 7.08 (d, J=4.80 Hz, 1H) 7.16-7.26(m, 2H) 7.38 (d, J=4.80 Hz, 1H) 7.44 (br. s., 1H) 7.55 (d, J=8.08 Hz, IH) 7.62 (d, J=6.82 Hz, 1H) 10.49 (br. s., 1H) 12.76 (s, 1H); MS (ES+):m/z 305.15 [MH⁺].

Example 9

1-(1,3-Benzoxazol-5-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

A mixture of 5-chlorobenzoxazole (0.129 g, 0.84 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (0.4956 g,1.95 mmol), potassium acetate (0.41 g, 4.2 mmol),1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene hydrochloride (43 mg,0.10 mmol) and palladium acetate (11 mg, 0.05 mmol) was degassed,treated with tetrahydrofuran (10 mL) and the resulting mixture heated at80° C. overnight. The mixture was diluted with water (100 mL), acidifiedto pH 6 and extracted with EtOAc (3×40 mL). The extracts were washedwith water, dried and concentrated in vacuo. The residue so obtained waspurified by chromatography over silica gel eluting with DCM to 10%MeCN/DCM to afford 1,3-benzoxazole-5-boronic acid, pinacol ester. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.37-1.39 (m, 12H) 7.59 (d, J=8.34 Hz, 1H)7.86 (dd, J=8.08, 1.01 Hz, 1H) 8.10 (s, 1H) 8.26 (s, 1H); MS (ES+): m/z246.23 [MH⁺].

This material was used in place of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole under theconditions described in example 1 to afford1-(1,3-benzoxazol-5-yl)-3-cyclobutylimidazo[1,5-a]pyran-8-amine MS(ES+): m/z 306.16 [MH+].

Example 10

{trans-4-[8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol

Prepared according to the procedure described in EXAMPLE 2 usingtrans-[4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanolin place of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. ¹H NMR(DMSO-d6, 400 MHz) δ1.12-1.23 (m), 1.38-1.54 (m, 1H); 1.58-1.78 (m, 2H);1.82-1.92 (m, 2H); 1.96-2.06 (m, 2H); 3.03-3.16 (m, 1H); 3.29 (t, J=5.6Hz, 2H); 4.46 (t, J=5.3 Hz, 1H); 6.45 (brs, 2H); 6.63 (d, J=1.38 Hz,1H); 7.02 (t, J=7.50 Hz, 1H); 7.06 (d, J=4.99 Hz, 1H); 7.12 (t, J=7.52,1H), 7.46 (d, J=8.02 Hz, 1H), 7.58 (d, J=7.83 Hz, 1M, 7.66 (d, J=5.06Hz, 1H), 11.43 (s, 1H); MS (ES+): m/z 362.07 (100) [MH+], HPLC:t_(R)=1.97 min (MicromassZQ, polar_(—)5min).

Example 11

{cis-3-[8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol

Prepared according to the procedure described in EXAMPLE 2 using[3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]methanol inplace of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+):m/z 334.10[MH+].

Example 12

cis-3-[8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol

Prepared according to the procedure described in EXAMPLE 2 using3-($-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanol in place of8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+): m/z 320.03[MH+].

Example 13

3-[cis-3-(4-Acetylpiperazin-1-yl)cyclobutyl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described in EXAMPLE 2 using1-{4-[3-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]piperazin-1-yl}ethanonein place of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+):m/z 430.08 [MH+].

Example 14

{trans-4-[S-Amino-1-(1H-indol-5-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol

Prepared according to the procedure described in EXAMPLE 1 usingtrans-[4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanolin place of 9-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+):m/z 362.07 [MH+].

Example 15

1-(1H-Indol-2-yl)-3-[cis-3-(methylpiperazin-1-yl)cyclobutyl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described in EXAMPLE 2 using1-iodo-3-[3-(4-methyl-piperazin-1-yl)cyclobutyl]imidazo[1,5-a]pyrazin-8-ylaminein place of 8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+):m/z 402.10 [MH+].

Example 16

7-Cyclobutyl-5-(1H-indol-5-yl)imidazo[5,1-f][1,2,4]triazin-4-amine

Prepared according to the procedure described in EXAMPLE 1 using7-cyclobutyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-ylamine in place of8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+): m/z 305.16[MH+].

Example 17

7-Cyclobutyl-5(1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-4-amine

Prepared according to the procedure described in EXAMPLE 2 using7-cyclobutyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine in place of8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+): m/z 305.07[MH+].

Example 18

7-Cyclobutyl-5-(1H-indol-6-yl)imidazo[5,1-f][1,2,4]triazin-4-amine

Prepared according to the procedure described in EXAMPLE 7 using7-cyclobutyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-ylamine in place of8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. MS (ES+): m/z 305.07[MH+].

Example 19

7-Cyclohexyl-5-(1H-indol-2-yl)imidazo[5,1-f][1,2,4]triazin-4-amine

Prepared according to the procedure described in EXAMPLE 2 using7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine in place of8-amino-3-cyclobutyl-1-iodoimidazo[3,4-a]pyrazine. ¹H NMR (400MHz-DMSO-d6) δ 1.40-1.54 (m, 4H), 1.72-1.82 (m, 2H), 1.87-1.92 (m, 2H),2.02-2.09 (m, 2H) 3.31-3.38 (m, 1H) 6.26 (bs, 2H) 6.73-6.74 (m, 1H),7.13-7.17 (m, 1H), 7.22-7.25 (m, 1H), 7.44 (d, J=8.0 Hz, 1H) 7.64 (d,J=8.0 Hz, 1H), 7.91 (s, 1H), 9.18 (s, 1H). MS (ES+): m/z: 333.16(100)[MH+]. HPLC: t_(R)=3.46 min (OpenLynx: polar_(—)5 min).

Example 20

A mixture of{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanol(400 mg, 0.001 mol), phthalimide (211.7 mg, 0.001439 mol), andtriphenylphosphine resin (2.14 mmol/g loading; 1.03 g, 0.00221 mol;Argonaut) in THF (22 mL, 0.27 mol; Aldrich) was placed under nitrogenatmosphere and charged dropwise with diisopropyl azodicarboxylate (290.9mg, 0.001439 mol). After 16 h, the resin was filtered off, washed withchloroform (5×20 mL) and the filtrate concentrated in vacuo to yield anorange oil which was chromatographed over silica gel eluting withchloroform→5% MeOH/chloroform to afford the title compound. ¹H NMR(CDCl₃, 400 MHz): δ 7.90-7.85 (m, 2H) 7.77-7.70 (m, 2H), 7.64 (m, 1H),7.43 (dd, J=8.0, 0.8 Hz, 1H), 7.27-7.15 (m, 2H), 7.14 (m, 1H), 7.09 (d,J=4.8 Hz, 1H), 6.77 (br s, 1H), 3.64 (d, J=6.4 Hz, 2H), 2.91 (m, 1H),2.09 (m, 2H), 2.25-1.90 (m, 4H), 1.80 (ddd, J=13.2, 12.4, 2.4 Hz, 2H),1.27 (ddd, J=13.2, 12.4, 2.4 Hz, 2H). MS (ES+): m/z 491.09 [MH+].

Example 21

1-{trans-4-[8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine

A solution of benzyl{[trans-4-(g-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate(0.163 g, 0.330 mmol) in cone. HCl (5 ml) was stirred at rt overnight.The reaction mixture was diluted with H₂O (20 mL), washed with Et₂O (30mL), then basified with 1N NaOH (aq) and extracted with DCM (3×20 mL).The combined extracts were washed with water then dried over Na₂SO₄ andconcentrated in vacuo To afford 0.085 g of desired compound. MS (ES+):m/z 361.30 [MH+].

Example 22

N-({trans-4-[8-Amino-1-(1H-indol-2-yl)imidazo[1,5a]pyrazin-3-yl]cyclohexyl}methyl)acetamide

To a suspension of1-{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine(100.00 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride (0.0798 g, 0.416 mmol), N,N-diisopropylethylamine (0.097mL, 0.55 mmol), 1-hydroxbenzotriaxole Hydrate (0.0425 g, 0.277 mmol),and DMF (600 uL) in DCM (5 mL) was added AcOH (24 uL). The mixture wasstirred at rt for 3 h under an atmosphere of nitrogen then diluted withDCM→(20 mL), washed with saturated NaHCO₃ (aq) (2×25 mL) and brine (2×25mL), then dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was chromatographed over silica gel eluting with DCM→2% 2M NH₃in MeOH/DCM to afford 0.02 g of the title compound. MS (ES+): m/z 403.31[MH+]. ¹H NMR (400 MHz, CDCl₃): δ 1.12-1.31 (m, 3H), 1.79-1.86 (m, 2H),1.94-1.97 (m, 2H), 2.02 (s, 3H), 2.04-2.09 (m, 2H), 2.91 (m, 1H), 3.20(t, J=6.4 Hz, 2H), 5.51 (hr, 1H), 5.66 (br, 2H), 6.79 (s, 1H), 7.10-7.16(m, 2H), 7.20-7.25 (m, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.44 (d, J=7.6 Hz,1H), 9.07 r, 1H).

Example 23

N-({4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5a]pyrazin-3-yl]cyclohexyl}methyl)methanesulfonamide

Methanesulfonyl chloride (4.40 L, 0.057 mmol was added to a mixture of1-{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine(20.5 mg, 0.057 mol) and PS-DIEA (3.90 mmol/g loading; 60 mg, 0.2 mmol)in DCM (1.14 mL). The reaction mixture was stirred for 30 min at r.t.for 18 h. The crude reaction mixture was then concentrated and residuepurified by mass directed preparative HPLC to afford 4 mg of desiredproduct MS (ES+): m/z 439.10 (100) [MH+]. ¹H NMR (CD3OD, 400 MHz): δ8.24 (br s, 2M, 7.61 (m, 2H), 7.46 (dd, J=8.4, 0.8 Hz, 1H), 7.19 (ddd,J=7.2, 1.2, 1.2 Hz, 1H), 7.08 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 6.75 (d,J=0.8 Hz, 1H), 3.14 (m, 1H), 2.07 (m, 4H), 1.85 (m, 2H), 1.64 (m, 1H),1.26 (m, 2H).

Example 24

Benzyl4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-carboxylate

A mixture of benzyl4-(8-amino-4-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate(1.149 g, 0.002191 mol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronicacid (0.629 g, 0.00241 mol), 1,2-dimethoxyethane (9.3 mL), water (1.8mL) and cesium carbonate (1.43 g, 0.00438 mol) was degassed three timesand then treated with tetrakis(triphenyl phosphine)palladium(0) (200 mg,0.0002 mol). The mixture was once more degassed and then heated at 100°C. overnight. The resulting reaction mixture was diluted with EtOAc (30mL) then washed with water (2×30 mL) and brine, dried over Na₂SO₄ andconcentrated in vacuo. The crude product was chromatographed over silicagel eluting with hexane→EtOAc hexane 1:1.0.05 2M NH₃/MeOH to afford thedesired product. ¹H NMR (400 MHz CDCl₃): δ 2.02-2.06 (m, 4H), 3.03-3.17(m, 3H), 4.29-4.33 (m, 2H), 5.16 (s, 2H), 5.66 (br, 2H), 6.79-6.80 (m,1H), 7.11-7.16 (m, 2H), 7.20-7.25 (m, 2H), 7.31-7.45 (n4, 5H), 7.44 (m,1H), 7.64 (d, J=7.6 Hz, 1H), 8.96 (br, 1H). MS (ES+): m/z 467.12 [MH+].

Example 25

1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5a]pyrazin-8-amine

A solution of benzyl4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]piperidine-1-carboxylate(3.61 g, 0.00774 mol) in conc. HCl (100 ml) was stirred at rt overnight.The mixture was then diluted with water (200 mL), washed with Et₂O (2×30mL) then the aqueous layer concentrated in vacuo yielding 2.62 g ofdesired product as the trihydrochloride salt ¹H NMR (400 MHz, MeOD): δ2.19-2.32 (m, 4H), 3.26-3.30 (m, 2H), 3.53-3.36 (m, 2H), 3.70 (m, 1H),7.06 (d, J=5.6 Hz, 1H), 7.10-7.14 (m, 1H), 7.23-7.26 (m, 2H), 7.50-7.52(m, 1H), 7.67 (m, 1H), 7.93 (m, 1H). MS (ES+): m/z 333.27 [MH+].

Example 26

4-[8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]piperidine-1-carbaldehyde

To a solution of1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-aminehydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 ml, 0.008 mol) wasadded N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL),1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid(4.7 mg, 0.10 mmol). The reaction was stirred at rt overnight thendiluted with DCM, washed with saturated NaHCO₃ (2×25 mL) and brine(2×25), then dried over Na₂SO₄ and concentrated in vacuo. The materialthus isolated was crystallized from EtOAc to afford 10.6 mg of desiredproduct. ¹H NMR (400 MHz, CDCl₃): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m,1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80(s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz,1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].

Example 27

3-[1-(1H-Indol-3-ylcarbonyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using indole-3-carboxylic acid in place of formic acid. MS (ES+):m/z 476.18 [MH+].

Example 28

3-(1-Acetylpiperidin-4-yl)-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using acetic acid in place of formic acid. MS (ES+): m/z 375.17[MH+].

Example 29

3-[1-(4-Methoxybenzoyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-methoxybenzoic acid in place of formic acid. MS (ES+):m/z 467.27 [MH+].

Example 30

3-[1-(4-Bromobenzoyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-methoxybenzoic acid in place of formic acid. MS (ES+):m/z 515.17 & 517.17 [MH+].

Example 31

1-(1H-Indol-2-yl-3-[1-(methoxyacetyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 2-methoxyacetic acid in place of formic acid. MS (ES+): m/z405.10 [MH+].

Example 32

3-[1-(Cyclopentylcarbonyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using cyclopentanecarboxylic acid in place of formic acid. MS(ES+): m/z 429.07 [MH+].

Example 33

3-{1-[(2,5-Dimethyl-1H-pyrrol-3-yl)carbonyl]piperidin-4-yl}-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 2,5-dimethylpyrrolecarboxylic acid in place of formic acid.MS (ES+): m/z 454.19 [MH+].

Example 34

3-{1-[4-(Dimethylamino)butanoyl]piperidin-4-yl}-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-gamine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-(dimethylamino)butanoic acid in place of formic acid. MS(ES+): m/z 446.22 [MH+].

Example 35

3-(1-[4-(Dimethylamino)phenacyl]piperidin-4-yl)-1-(1H-indol-2-yl)imidazo[1-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-(dimethylamino)phenylacetic acid in place of formic acid.MS (ES+): m/z 480.22 [MH+].

Example 36

3-{1-[4-Dimethylamino)benzoyl]piperidin-4-yl}-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4(dimethylamino)benzoic acid in place of formic acid. MS(ES+): m/z 480.22 [MH+].

Example 37

3-[1-(Cyclohexylcarbonyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using cyclohexanecarboxylic acid in place of formic acid. MS(ES+): m/z 443.20 [MH+].

Example 38

3-[1-(Cyclopropylcarbonyl)piperidin-4-yl]-1-(1-H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using cyclopropanecarboxylic acid in place of formic acid. MS(ES+): m/z 401.19 [MH+].

Example 39

1-(1H-Indol-2-yl)-3-[1-(2-thienylcarbonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using thiophene-2-carboxylic acid in place of formic acid. MS(ES+): m/z 443.22 [MH+].

Example 40

3-[1-(1H-Indol-3-ylacetyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using indole-3-acetic acid in place of formic acid. MS (ES+): m/z490.10 [MH+].

Example 41

1-(1H-Indol-2-yl)-3-{1-[(3-methoxyphenoxyacetyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using (3-methoxyphenoxy)acetic acid in place of formic acid. MS(ES+): m/z 497.11 [MH+].

Example 42

3-[1-(1,3-Benzodioxol-5-ylcarbonyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 1,3-benzodioxole-5-carboxylic acid in place of formic acid.MS (ES+): m/z 481.05 [MH+].

Example 43

1-(1H-Indol-2-yl)-3-{1-[(1-methyl-1H-indazol-3-yl)carbonyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 1-methyl-1H-indazole-3-carboxylic acid in place of formicacid. MS (ES+): m/z 491.04 [MH+].

Example 44

1-(1H-Indol-2-yl)-3-{1-[(3-methoxyphenyl)acetyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 3-methoxyphenylacetic acid in place of formic acid. MS(ES+): m/z 481.09 [MH+].

Example 45

3-[1-(1-Benzothien-3-ylcarbonyl)piperidin-4-yl]-1-iodoimidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using benzothiophene-3-carboxylic acid in place of formic acid.MS (ES+): m/z 493.01 [MH+].

Example 46

3-[1-(1,3-Benzothiazol-6-ylcarbonyl)piperidin-4-yl]-1-iodoimidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using benzothiazole-6-carboxylic acid in place of formic acid. MS(ES+): m/z 494.01 [MH+].

Example 47

1-(1H-Indol-2-yl)-3-{1-[2-methylcyclohexa-2,5-dien-1-yl)carbonyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 2-methylcyclohexa-2,5-diene-1-carboxylic acid in place offormic acid. MS (ES+): m/z 453.08 [MH+].

Example 48

1-(1H-Indol-2-yl)-3-[1-(isoquinolin-1-ylcarbonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using isoquinoline-1-carboxylic acid in place of formic acid. MS(ES+): m/z 488.01 [MH+].

Example 49

1-(1H-Indol-2-yl)-3-{1-[(pyridin-4-ylthio)acetyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using (pyridin-4-ylthio)acetic acid in place of formic acid. MS(ES+): m/z 484.04 [MH+].

Example 50

1-(1H-Indol-2-yl)-3-[1-(pyridin-3-ylacetyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using pyridin-3-ylacetic acid in place of formic acid. MS (ES+):m/z 452.07[MH+].

Example 51

4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)N,N-dimethylpiperidine-1-carboxamide

A mixture of1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-aminehydrochloride (30.0 mg, 0.0679 mmol),N,N-diisopropylethylamine (59.1 μL,0.340 mmol) and DMF (1.00 mL) was treated with N,N-dimethylcarbamoylchloride (6-23 μL, 0.0679 mmol) and stirred at rt for 1 h prior tosemi-preparative HPLC to afford the isolated title compound. ¹H NMR (400CD₃OD) ppm: 8.32 (br. s., 1H), 7.59-7.66 (m, 2H), 7.46 (d, 1H, J=8.3Hz), 7.15-7.22 (m, 1H), 7.01-7.10 (m, 2H), 6.74 (s, 1H), 3.82 (d, 2H,J=12.6 Hz), 3.34-3.42 (m, 1H), 2.97-3.09 (m, 2H), 2.87 (s, 6H),1.95-2.09 (m, 4H); MS (ES+): m/z 404.14 [MH+].

Example 52

Methyl4(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate

A mixture of1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-aminehydrochloride (30.0 mg, 0.0679 mmol), N,N-diisopropylethylamine (59.1μL, 0.3440 mmol) and DMF (1.00 mL) was treated with methyl chloroformate(5.25 μL, 0.0679 mmol) and stirred at rt for 1 h prior tosemi-preparative HPLC to afford the isolation of the title compound. ¹HNMR (400 MHz, CD₃OD) ppm: 8.32 (br. s., 1H), 7.58-7.66 (m, 2H), 7.46 (d,1H, J=8.1 Hz), 7.14-7.22 (m, 1H), 7.00-7.12 (m, 2H), 6.73 (s, 1H), 4.26(d, 2H, J=12.9 Hz), 3.71 (s, 3H), 3.33-3.37 (m, 3H), 2.9-3.17 (m, 2H),1.85-2.06 (m, 4H); MS (ES+): m/z 391.06 [MH+].

Example 53

3-[1-(4-Chloro-2-methylbenzoyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-chloro-2-methylbenzoic acid in place of formic acid. MS(ES+): m/z 485.05 [MH+].

Example 54

1-(1H-Indol-2-yl)-3-(1-{[1-(4-methylphenyl)cyclopropyl]carbonyl}piperidinyl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 1-(4-methylphenyl)cyclopropanecarboxylic acid in place offormic acid. MS (ES+): m/z 491.11 [MH+].

Example 55

3-[1-(4-Chloro-3-methoxybenzoyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-chloro-3-methoxybenzoic acid in place of formic acid. MS(ES+): m/z 501.04 [MH+].

Example 56

1-(5-{[4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)piperidin-1-yl]carbonyl}-2-thienyl)ethanone

Prepared according to the procedure described above for EXAMPLE 26,except using 5-acetylthiophene-2-carboxylic acid in place of formicacid. MS (ES+): m/z 485.04 [MH+].

Example 57

1-(1H-Indol-2-yl)-3-[1-(3-thienylcarbonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using thiophene-3-carboxylic acid in place of formic acid. MS(ES+): m/z 443.04 [MH+].

Example 58

1-(1H-Indol-2-yl)-3-[1-(4-nitrobenzoyl)piperidin-4-yl]-imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 26,except using 4-nitrobenzoic acid in place of formic acid. MS (ES+): m/z482.07 [MH+].

Example 59

3-[1-(Butylsulfonyl)piperidin-4-yl]-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

A solution of1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-aminehydrochloride (33.233 mg, 0.075 mmol) in DMF (1 mL) was treated withN,N-diisopropylethylamine (0.05 mL, 0.3 mmol) and a solution of^(n)butanesulfonyl chloride (9.42 mg, 0.0602 mmol) in 1 mL of DMF. Themixture was left to stir at rt for 1 h and then subjected tomass-directed preparative HPLC to afford the title compound. ¹H NMR (400MHz-DMSO-d6) δ 0.91 (t, 3H), 1.40-1.45 (m, 2H), 1.66-1.69 (m, 2H),1.86-1.90 (m, 2H) 2.04-2.09 (m, 2H) 3.02-3.11 (m, 5H) 3.73-3.77 (m, 2H),6.47 (bs, 2M, 6.64 (s, 111, 7.00-7.05 (m, 1H) 7.09-7.12 (m, 2H), 7.45(d, J=8.4 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.69 (d, J=5.2 Hz, 1H). MS(ES+): m/z: 453.24 [MH+].

Example 60

1-(1H-Indol-2-yl)-3-[1-(isopropylsulfonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using isopropane-2-sulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 439.27 [MH+].

Example 61

3-{1-[(—Fluorophenyl)sulfonyl]piperidin-4-yl}-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 4-fluorobenzenesulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 491.15 [MH+].

Example 62

3-{1-[(2,5-Dimethoxyphenyl)sulfonyl]piperidin-4-yl}-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 2,5-dimethoxybenzenesulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 533.17 [MH+].

Example 63

1-(1H-Indol-2-yl)-3-{1-[(4-methylphenyl)sulfonyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 4-methylbenzenesulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 487.94 [MH+].

Example 64

3-{1-[(3-Fluorophenyl)sulfonyl]piperidin4-yl}-1-(1H-Indol-2-yl)imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 3-fluorobenzenesulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 491.92 [MH+].

Example 65

3-Cyclobutyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)imidazo[1,5-a]pyrazin-8-amine

3-Cyclobutyl-1-[1-(2-trimethylsilylethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]imidazo[1,5-a]pyrazin-8-amine(35 mg, 0.08 mmol) was stirred with concentrated HCl for 15 min. Themixture was thien concentrated in vacuo and purified via mass directedpreparative HPLC to afford the title compound. ¹H NMR (400 MHz DMSO-d6)δ 1.92-2.00 (m, 1H), 2.07-2.14 (m, 1H), 2.43-2.47 (m, 4H), 3.93-4.01 (m,1H), 6.35-6.49 (Us, 2H), 6.64-6.70 (m, 1H), 7.03-7.10 (m, 2H), 7.39-7.49(m, 1H), 7.95-8.00 (m, 1H), 8.18-8.23 (m, 1H), 11.91 (bs, 1H). MS (ES+):m/z: 305.17 [MH+].

Example 66

Methyltrans-4(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate

Starting from trans-methyl4-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate, the titlecompound was prepared according to procedures analogous to thosedescribed for EXAMPLE 10. ¹H NMR (d₆-DMSO, 400 MHz): δ 11.42 (br s, 1H),7.70 (d, J=4.0 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H),7.30-4.90 (m, 3H), 6.63 (br s, 1H), 6.44 (br s, 1H), 3.64 (s, 3H), 3.18(m, 1H), 2.44 (m, 1H), 2.03 (m, 4H), 1.80-1.50 (m, 4H). MS (ES+): m/z390.28 [MH+].

Example 67

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylicAcid

A mixture of 37% HCl (30 mL) and methyltrans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate(500.0 mg, 1.28 mmol) was stirred for 18 h at rt. The reaction mixturewas then concentrated in vacuo, and the residue washed with diethylether (3×10 mL) and ethyl acetate (2×10 mL), then with ice-coldacetonitrile (10 mL) to afford 0.3 g of the desired product. ¹H NMR(d6-DMSO, 400 MHz): δ 12.15 (br s, 1H), 11.69 (s, 1H), 8.45 (br s, 2H),7.97 (d, J=6.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.50 (dd, J=8.0, 0.4 Hz,1H), 7.19 (m, 1H), 7.13 (d, J=6.0 Hz, 1H), 7.06 (m, 1H), 6.83 (d, J=1.6Hz, 1H), 3.27 (td, J=11.6, 3.2, 3.2 Hz, 1H), 2.33 (td, J=10.8, 3.2, 3.2Hz, 1H), 2.05 (m, 4H), 1.73 (m, 2H) and 1.58 (m/z, 2H). MS (ES+): m/z376.05 [MH+].

Example 68

trans-4(8-Amino-1-(Yl-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)-N-pyridin-3-ylcyclohexanecarboxamide

A suspension of 3-aminopyridine (40 mg, 0.43 mmol) in toluene (1.3 mL)was treated with a 2M toluene solution of trimethylaluminum (0.3 mL,0.60 mmol). After 25 min, the resulting solution was treated with methyltrans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylate(30 mg, 0.08 mol) and the mixture stirred at rt overnight. The mixturewas then stirred with 2M NaOH (20 mL) and ethyl acetate (20 mL) for 110min., then the organic phase was separated and the aqueous extractedEtOAc (3×15 nm). The combined organic extracts were washed with water(20 mL) and brine (20 mL), then dried over Na₂SO₄ and concentrated invacuo to give crude product which was subjected to mass-directedpreparative HPLC to afford pure desired product. ¹H NMR (d₆-DMSO, 400MHz): δ 11.45 (br s, 1H), 10.12 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.25(d, J=4.8 Hz, 1H), 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.6 Hz, 1H), 7.71 (d,J=5.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.34 (m,1H), 7.15-7.00 (m, 3H), 6.65 (s, 1H), 6.42 (br s, 2H), 3.22 (m, 1H),2.47 (m, 1H), 2.15-1.95 (m, 4H), and 1.85-1.65 (m, 4H). MS (ES+): m/z452.17 [MH+].

Example 69

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)-N-pyridin-2-ylcyclohexanecarboxamide

Prepared according to the procedure described above for EXAMPLE 68,except using 2-aminopyridine in place of 3-aminopyridine. MS (ES+): m/z452.17 [MH+].

Example 70

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)-N-phenylcyclohexanecarboxamide

Prepared according to the procedure described above for EXAMPLE 68,except using aniline in place of 3-aminopyridine. MS (ES+): m/z 451.16[MH+].

Example 71

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-apyrazin-3-yl]cyclohexanecarboxamide

trans-4-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxamide(40 mg, 0.10 mmol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (33mg, 0.12 mmol), and sodium carbonate (33 mg, 0.31 mmol) were added toDME:Water (5:1) (2 mL) and the mixture degassed with Argon for 10 min.Tetrakis(triphenylphosphine)palladium(0) (8.0 mg, 0.007 mmol) was thenadded and the reaction mixture microwaved at 110° C. for 1 h, Themixture was concentrated in vacuo, taken up in DMSO, and purified bymass-directed preparative HPLC to afford desired product. ¹H NMR(d₆-DMSO, 400 MHz): □ 11.50 (br s, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 7.46(dd, J=7.6, 0.4 Hz, 1H), 7.25 (br s, 1H), 7.13 (m, 1H), 7.08-7.00 (m,2H), 6.70 (br s, 1H), 6.69 (br s, W, 3.16 (m, 1H), 2.20 (m, 1H),2.10-1.80 (m, 4H) and 1.65 (m, 4H). MS (ES+): m/z 375.17 [MH+].

Example 72

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)-N-ethylcyclohexanecarboxamide

Ethylamine hydrochloride (30 mg, 0.37 mmol),2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(35 mg, 0.11 mmol), and N,N-diisopropylethylamine (80 μL, 0.53 mmol)were added to a solution oftrans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylicacid (25 mg, 0.07 mmol) in anhydrous DMF (2 mL). Upon completion ofreaction (as monitored by LCMS), the mixture was added to a saturatedaqueous sodium bicarbonate solution (10 mL). The resulting precipitatewas collected by filtration and washed with cold acetonitrile (3×10 mL)to afford 13 mg of the desired product. ¹H NMR (d₆-DMSO, 400 MHz): δ11.41 (br s, 1H), 7.75 (dd, J=4.0, 4.0 Hz, 1H), 7.69 (d, J=4.0 Hz, 1H),7.58 (d, J=8.0, 4.0 Hz, 1H), 7.45 (d, J=4.0, 4.0 Hz, 1H), 7.12 (dd,J=8.0, 8.0 Hz, 1H), 7.08-7.00 (m, 2H), 6.63 (m, 1H), 6.43 (br s, 2H),3.16 (m, 1H), 3.07 (m, 2H), 2.18 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H),1.66 (m, 4H) and 1.02 (t, J=4.0 Hz, 3H). MS (ES+): m/z 403.09 [MH+].

Example 73

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5a]pyrazin-3-yl)-N-cyclopropylcyclohexanecarboxamide

Prepared according to the procedure described above for EXAMPLE 72,except using cyclopropylamine in place of ethylamine. MS (ES+): m/z415.22 [MH+].

Example 74

Benzyl{[trans-4(8-amino-1-(1H-indol-2-yl)imidazo[1,5a]pyrazin-3-yl)cyclohexyl]methyl}carbamate

A mixture of benzyl{[trans-4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate(1.00 g, 0.00180 mol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid(0.517 g, 0.00198 mol), 1,2-dimethoxyethane (7.7 mL), water (1.4 mL,0.081 mol) and Cesium Carbonate (1.17 g, 0.00360 mol) degassed threetimes, treated with tetrakis (triphenylphosphine)palladium(0) (200 mg,0.0002 mol) and degassed once more. The resulting mixture was heated at100° C. overnight before being diluted with EtOAc (40 mL), washed withwater (2×30 mL) and brine (20 mL) then dried over Na₂SO₄ andconcentrated in vacuo. The crude product thus isolated waschromatographed over silica gel eluting with hexane→EtOAc:hexane: 5% 2MNH₃ in MeOH 1:1:0.05 to afford the title compound. ¹H NMR (400 MHz,CDCl₃): δ 1.13-1.22 (m, 2H), 1.75-1.86 (m, 2H), 1.94-1.97 (m, 2H),2.11-2.13 (m, 2H), 2.86 (m, 1H), 3.12-3.16 (m, 2H), 4.82 (m, 1H) 5.12(s, 2H), 5.69 (br, 2H), 6.78 (s, 1H), 7.13-7.15 (m, 2H), 7.19-7.25 (m,2H), 7.32-7.38 (m, 5H), 7.42 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H),9.09 (br, 1H). MS (ES+): m/z 495 [MH+].

Example 75

N-{[trans-4-(8-Amino]-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexylmethyl}-3-furamide

Prepared according to the procedure described above for EXAMPLE 22,except using 2-furoic acid in place of acetic acid. MS (ES+): m/z 455.20[MH+].

Example 76

N-{[trans-4(8-Amino-1-(1-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}benzamide

Prepared according to the procedure described above for EXAMPLE 22,except using benzoic acid in place of acetic acid. MS (ES+): m/z 465-25[MH+].

Example 77

N-{[trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5a]pyrazin-3-yl)cyclohexyl]methyl}cyclobutanecarboxamide

Prepared according to the procedure described above for EXAMPLE 22,except using cyclobutanecarboxylic acid in place of acetic acid. MS(ES+): m/z 443.25 [MH+].

Example 78

N-{[trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}-3,5-dimethoxybenzamide

Prepared according to the procedure described above for EXAMPLE 22,except using 3,5-dimethoxybenzoic acid in place of acetic acid. MS(ES+): m/z 525.35 [MH+].

Example 79

N-{[trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}-2,4-dimethoxybenzamide

Prepared according to the procedure described above for EXAMPLE 22,except using 2,4-dimethoxybenzoic acid in place of acetic acid. MS(ES+): m/z 525.33 [MH+].

Example 80

N-{[trans-4(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}formamide

Prepared according to the procedure described above for EXAMPLE 22,except using formic acid in place of acetic acid. MS (ES+): m/z 389.10[MH+].

Example 81

(1R,2R)—N-{[trans-4-(8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}-2-phenylcyclopropanecarboxamide

Prepared according to the procedure described above for EXAMPLE 22,except using (1R,2R)-2-phenylcyclopropanecarboxylic acid in place ofacetic acid. MS (ES+): m/z 505.30 [MH+].

Example 82

N-{[trans-4-(8-Amino-1-1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}-3-chloro-6-fluorobenzo[b]thiophene-2-carboxamide

Prepared according to the procedure described above for EXAMPLE 22,except using 3-chloro-6-fluorobenzo[b]thiophene-2-carboxylic acid inplace of acetic acid. MS (ES+): m/z 573.35 & 575.31 [MH+].

Example 83

N-{[trans-4-(8-Amino-1-(If-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}isoquinoline-2-carboxamide

Prepared according to the procedure described above for EXAMPLE 22,except using isoquinoline-2-carboxylic acid in place of acetic acid. MS(ES+): m/z 516.40 [MH+].

Example 84

N-{[trans-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}indole-3-carboxamide

Prepared according to the procedure described above for EXAMPLE 22,except using indole-3-carboxylic acid in place of acetic acid. MS (ES+):m/z 505.46 [MH+].

Example 85

1-(4-Chloro-1H-indol-2-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 2,except using 1-(tert-butoxycarbonyl)-4-chloro-1H-indole-2-boronic acidin place of 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid. ¹H NMR(400 MHz-DMSO-d6) δ 1.91-1.98 (m, 1H), 2.08-2.15 (m, 1H), 2.42-2.46 (m,4H), 3.97-4.00 (m, 1H), 6.42 (bs, 2H, 6.67 (s, 1H), 7.09-7.14 (m, 3H),7.43-7.47 (m, 2H) and 11.83 (bs, 1H). MS (ES+): m/z 338.26 [MH+].

Example 86

1-(1H-Indol-2-yl)-3-[1-(4-methoxyphenyl)cyclopropyl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 2,except using 4-methoxyphenyl)cyclopropanecarboxylic acid in place ofcyclobutanecarboxylic acid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46(s, 2H), 1.58 (s, 2H), 3.76 (s, 3H), 6.78 (d, J=8.80 Hz, 2H), 6.77 (s,1H), 6.82 (s, 1H), 6.98 (d, J=5.13 Hz, 1H), 7.03 (d, J=8.80 Hz, 2H),7.15 (t, J=7.52 Hz, 1H), 7.23 (s, 2H), 7.44 (d, J=8.07 Hz, 1H), 7.65 (d,J=8.07 Hz, 1H) and 9.36 (br. s., 1H). MS (ES+): m/z 396.15 [MH+].

Example 87

1-(1H-Indol-2-yl)-3-[1-(propylsulfonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using propane-2-sulfonyl chloride in place of ^(n)butanesulfonylchloride. MS (ES+): m/z 439.06 [MH+].

Example 88

1-(1H-Indol-2-yl)-3-[1-(phenylsulfonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using benzenesulfonyl chloride in place of ^(n)butanesulfonylchloride. MS (ES+): m/z 473.29 [MH+].

Example 89

1-(1H-Indol-2-yl)-3-{1-[(3,3,3-trifluoropropyl)sulfonyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 3,3,3-trifluoropropane-1-sulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 493.19 [MH+].

Example 90

trans-3-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)-N-[(1S)-1-phenylethyl]cyclohexanecarboxamide

Prepared according to the procedure described above for EXAMPLE 72,except using (1S)-4-phenylethanamine in place of cyclopropylamine. MS(ES+): m/z 479.11 [MH+].

Example 91

N-{[trans-4(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methyl}(3-bromophenyl)acetamide

Prepared according to the procedure described above for EXAMPLE 22,except using 3-bromophenylacetic acid in place of acetic acid. MS (ES+):m/z 557.21 and 559.20 [MH+].

Example 92

N-{[trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5a]pyrazin-3-yl)cyclohexyl]methyl}(2,6-dichloro-5-fluoropyridin-3-yl)acetamide

Prepared according to the procedure described above for EXAMPLE 22,except using (2,6-dichloro-5-fluoropyridin-3-yl)acetic acid in place ofacetic acid. MS (ES+): m/z 522.21 [MH+].

Example 93

Benzyl4-[8-amino-1-(1H-indol-5-yl)imidazo[1,5-a]pyrazin-3-yl]piperidine-1-carboxylate

Prepared according to the procedure described above for EXAMPLE 24,except using indole-5-boronic acid in place of1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid. MS (ES+): m/z 494.97[MH+].

Example 94

trans-4-(8-Amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl)-N-benzimidazol-2-ylcyclohexanecarboxamide

Prepared according to the procedure described above for EXAMPLE 68,except using 2-aminobenzimidazole in place of 3-aminopyridine. MS (ES+):m/z 490.97 [MH+].

Example 95

1-(1H-Indol-2-yl)-3-[1-(quinolin-2-ylmethyl)piperidin-4-yl]imidazo[1,5a]pyrazin-8-amine

A solution of1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-aminehydrochloride (30 mg, 0.09 mmol), 2-formylquinoline (17 mg, 0.11 mmol)and triethylamine (0.019 mL, 0.14 mmol) in 1,4-dioxane (1 mL) wastreated with sodium cyanoborohydride (5.7 mg, 0.090 mmol) and microwavedat 300 watts, 120° C. for 20 min. The mixture was concentrated in vacuo,the residue was dissolved in methanol loaded onto an SCX ion exchangecartridge, and then eluted with 1M NH₄OH in methanol. The semi-purematerial thus obtained was then subjected to semi-preparative HPLC toafford desired product. ¹H NMR (400 h MeOD) δ ppm 2.13-2.33 (m, 4H),2.90 (t, J=10.86, 9.60 Hz, 2H), 3.47 (d, J=10.11 Hz, 2H), 4.29 (s, 2H),6.74 (s, 1H), 7.02-7.11 (m, 2H), 7.19 (t, J=8.08, 7.07 Hz, 1H), 7.47 (d,J=39.09 Hz, 1H), 7.58-7.65 (m, 3H), 7.69 (d, J=8.59 Hz, 1H), 7.80 (t,J=8.34, 6.82 Hz, 1H), 7.96 (d, J=7.33 Hz, 1H), 8.08 (d, J=8.34 Hz, 1H)and 8.39 (d, J=8.59 Hz, I H). MS (ES+): m/z 474.23 [MH+].

Example 96

1-(1H-Indol-2-yl)-3-[1-(2-thienylsulfonyl)piperidin-4-yl]imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using thiophene-2-sulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 479.16 [MH+].

Example 97

1-(1H-Indol-2-yl)-3-{1-[(3-methylphenyl)sulfonyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 3-methylbenzenesulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 487.94 [MH+].

Example 98

1-(1H-Indol-2-yl)-3-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}imidazo[1,5-a]pyrazin-8-amine

Prepared according to the procedure described above for EXAMPLE 59,except using 1-methyl-1H-imidazole-4-sulfonyl chloride in place of^(n)butanesulfonyl chloride. MS (ES+): m/z 477.20 [MH+].

The following examples were prepared according to procedures analogousto those described above, utilizing where necessary known literaturechemistries.

Ex # Structure MH+  99

500.93 502.91 100

433.06 101

433.02 102

404.96 103

474.23 104

483.00 105

483.27 106

452.04 107

514.92 108

500.89 109

492.92 110

447.01 111

498.93 500.90 112

456.90 113

420.97 114

496.91 115

488.91 116

475.91 117

468.84 118

426.99 119

461.00 120

320.86 121

391.23 122

490.97 123

493.18 124

487.09 125

459.01 126

446.15 127

452.98 128

451.97 129

481.95 130

470.00 131

535.91 132

454.97 133

448.02 134

318.03 135

470.96 136

475.92 137

475.92 138

457.08 139

426.92 140

521.03 523.08 141

427.05 142

457.02 143

444.20 144

425.91 145

376.98 146

337.97 339.92 147

304.95 148

452.95 149

305.20 150

389.83 151

426.97 152

456.79 153

443.97 154

475.94 155

492.76 156

475.85 157

460.13 158

375.98 159

466.97 160

451.98 161

304.19 162

405.02 163

433.18 164

532.90 165

476.95 166

410.02 167

321.92 168

333.87 169

381.83 383.72 170

459.97 171

465.96 172

468.84 470.50 173

480.20 174

452.97 175

466.20 176

339.92 177

426.91 178

472.62 179

550.68 552.50 180

456.63 181

471.89 182

523.93 183

496.05 184

510.00 185

483.89 186

404.18 187

427.93 188

428.88 189

460.66 191

548.72 192

456.86 193

525.25 194

467.21 195

486.96 196

470.97 197

444.00 198

363.89 199

403.07 200

458.97 201

500.96 202

500.94 203

362.03 204

473.95 205

335.06 206

433.07 207

486.96 208

348.02 209

473.87 210

334.88 211

457.95 212

318.92 213

475.02 214

425.17 427.06 215

518.83 216

379.87 217

439.19 218

526.77 219

483.04 220

520.89 221

436.98 438.94 222

425.93 223

411.13 413.02 224

453.99 225

433.02 226

479.85 227

434.95 228

417.21 229

500.99 502.88 230

516.91 518.90 231

498.02 232

440.89 442.86 233

354.74 356.98 234

335.84 235

442.96 236

480.98 237

421.83 238

549.91 239

480.02 240

419.89 241

467.92 242

420.97 243

487.97 244

319.00 245

405.03 246

499.95 501.96 247

423.83 425.93 248

409.95 411.90 249

376.99 250

412.06 414.03 251

404.96 252

391.01 253

419.12 254

434.04 255

405.03 256

445.01 257

438.94 440.89 258

406.98 406.99 259

421.00 260

437.93 439.95 261

511.21 513.14 262

447.03 263

461.05 264

447.99 265

462.00 266

387.20 267

432.06 268

434.02 434.06 269

437.97 439.95 270

468.95 271

423.97 425.93 272

448.05 273

471.98 274

418.09 275

405.03 276

363.98 277

423.97 425.99 278

391.01 279

460.94 280

421.00 281

435.03 282

485.32 283

510.38 284

406.29 285

404.21 286

420.53 287

417.29 288

423.29 289

455.11 457.09 290

497.93 291

424.04 425.99 292

434.08 293

475.89 294

461.94 295

485.14 487.10 296

491.18 297

488.63 298

434.08 299

435.10 300

505.10 301

438.00 302

432.02 303

467.30 304

455.23 305

405.09 306

424.13 426.23 307

458.99 308

409.97 411.96 309

445 445.1 310

407.05 311

421.00 312

512.40 313

418.03 314

391.06 315

453.04 453.17 453.39 316

474.95 317

457.08 318

457.95 319

482.96 320

483.90 321

390.02 322

463.08 323

460.09 324

480.21 325

471.11 326

455.94 327

486.20 328

436.23 438.26 329

432.02 330

402.06 331

452.12 332

434.25 333

406.35 406.42 334

501.31 335

487.44 336

420.15 420.18 337

411.06 413.07 338

471.35 339

454.07 456.03 340

484.44 341

470.41 342

469.46 343

409.35 344

416.17 345

485.39 346

444.10 347

471.41 348

404.04 406.06 349

404.27 406.29 350

469.39 351

401.39 352

444.16 353

481.12 483.14 354

415.17 355

400.09 356

425.34 427.33 357

417.36 358

402.33 359

381.96 384.01 360

487.01 489.03 361

495.03 362

428.02 363

458.32 364

487.01 488.90 365

470.37 366

521.27 523.27 367

443.22 368

459.28 369

458.37 370

493.22 495.18 371

471.03 372

510.03 373

496.06 374

501.45 375

493.49 376

507.46 377

569.56 378

507.46 379

521.50 380

583.53 381

425.39 382

439.42 383

555.55 384

569.55

[1] The following compounds are expected to be active as inhibitors ofmTOR. Where shown, X can be N or CH.

1-21. (canceled)
 22. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 23. The compound of claim22, which is selected from:

or a pharmaceutically acceptable salt thereof.
 24. The compound of claim22, which is selected from:

or a pharmaceutically acceptable salt thereof.
 25. The compound of claim22, which is selected from:

or a pharmaceutically acceptable salt thereof.
 26. The compound of claim22, which is selected from:

or a pharmaceutically acceptable salt thereof.